Glucamine compounds for treating hepatitis virus infections

ABSTRACT

N-Substituted glucamine compounds of Formula I are effective in treatment of hepatitis infections, including hepatitis B and hepatitis C. In treating hepatitis infections, the compounds of Formula I may be used alone, or in combination with another antiviral agents selected from among nucleosides, nucleotides, immunomodulators, immunostimulants or various combinations of such other agents.

This application claims the benefit of provisional applications60/119,858 filed Feb. 12, 1999 and 60/119,836 May 3, 1999.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to methods and compositions for treatinghepatitis virus infections, especially hepatitis B virus infections, inmammals, especially humans. The methods comprise administering glucaminecompounds in combination with nucleoside antiviral agents, nucleotideantiviral agents, mixtures thereof, orimmunomodulating/immunostimulating agents. Such combinations ofanti-hepatitis viral agents show unexpected efficacy in inhibitingreplication and secretion of hepatitis viruses in cells of mammalsinfected with these viruses.

2. Background of Invention

Over half the biologically important proteins are glycosylated and thatglycosylation may vary with disease. Based upon this information, theuse of drugs to control of glycosylation patterns, glycoforms, changesor rates of change will have a a biochemical effect and may provide abeneficial therapeutic result. Control of glycolipid and glycoproteinsugar patterns as well as their synthesis and degradation leads to basicphysiological effects on mammals including humans, agricultural animalsand pets. Possibly, this is through influences on, for example, N-linkedglycans, O-linked glycans, glucosoaminoglycans, glycosphingolipids,glycophospholipids, lectins, immuneoglobulin molecules, antibodies,glycoproteins and their biochemical intermediates or conversionproducts. Modification of glycosalation site occupancy influencesreceptor and enzyme binding site specificity, selectivity, capacity,protein folding, enzyme activity, kinetics and energetics. Glycosidaseand glycosyltransferase systems are two biochemical mechanisms that aresuggested to affect such systems (Dwek, Raymond A., Glycobiology: TowardUnderstanding the Function of Sugars, Chemical Reviews, 96,683-720(1996).

Iminosugars are anti-viral drugs that can induce the inhibition of viralinteractions with and within mammalian cells such as attachment tocells, penetration of cells, maturation within cells and release fromcells. The mechanism involved may be glucosidase inhibition, glycosyltransferase inhibition or others as discussed above.

Hepatitis B Virus (HBV, HepB) is a causative agent of acute and chronicliver disease including liver fibrosis, cirrhosis, inflammatory liverdisease, and hepatic cancer that can lead to death in some patients(Joklik, Wolfgang K., Virology, Third Edition, Appleton & Lange,Norwalk, Conn., 1988 (ISBN 0-8385-9462-X)). Although effective vaccinesare available, there are still more than 300 million people worldwide,i.e., 5% of the world's population, chronically infected with the virus(Locarnini, S. A., et. al., Antiviral Chemistry & Chemotherapy (1996)7(2):53-64). Such vaccines have no therapeutic value for those alreadyinfected with the virus. In Europe and North America, between 0.1% to 1%of the population is infected. Estimates are that 15% to 20% ofindividuals who acquire the infection develop cirrhosis or anotherchronic disability from HBV infection. Once liver cirrhosis isestablished, morbidity and mortality are substantial, with about a5-year patient survival period (Blume, H., E., et.al., Advanced DrugDelivery Reviews (1995) 17:321-331). It is therefore necessary and ofhigh priority to find improved and effective anti-hepatitis therapies(Locarnini, S. A., et. al., Antiviral Chemistry & Chemotherapy (1996)7(2): 53-64).

Other hepatitis viruses significant as agents of human disease includeHepatitis A, Hepatitis B, Hepatitis C, Hepatitis Delta, Hepatitis E,Hepatitis F, and Hepatitis G (Coates, J. A. V., et.al., Exp. Opin. Ther.Patents (1995) 5(8):747-756). Hepatitis C infection is also on theincrease and effective treatments are needed. In addition, there areanimal hepatitis viruses that are species-specific. These include, forexample, those infecting ducks, woodchucks, cattle and mice.

Glucamine Compounds

Glucamine (also known as 1-deoxynojirimycin, DNJ) and its N-alkylderivatives (together, “imino sugars”) are known inhibitors of theN-linked oligosaccharide processing enzymes alpha glucosidase I and II(Saunier et al., J. Biol.Chem. (1982) 257:14155-14161 (1982); Elbein,Ann. Rev. Biochem. (1987) 56:497-534). As glucose analogs, they alsohave potential to inhibit glucose transport, glucosyl-transferases,and/or glycolipid synthesis (Newbrun et al., Arch. Oral Biol. (1983) 28:516-536; Wang et al., Tetrahedron Lett. (1993) 34:403-406). Theirinhibitory activity against glucosidases has led to the development ofthese compounds as anti-hyperglycemic agents and antiviral agents. See,for example, PCT International Publication WO 87/03903 and U.S. Pat.Nos. 4,065,562; 4,182,767; 4,533,668; 4,639,436; 4,849,430; 4,957,926;5,011,829; and 5,030,638.

Glucosidase inhibitors such as N-alkyl-glucamine compounds wherein thealkyl group contains between three and six carbon atoms have been shownto be effective in the treatment of Hepatitis B infection (PCTInternational Publication WO 95/19172). For example,N-(n-butyl)-deoxynojirimycin (N-butyl-DNJ;N-(n-butyl)-1-5-dideoxy-1,5-imino-D-glucitol) is effective for thispurpose (Block, T. M., Proc. Natl. Acad. Sci. USA (1994) 91:2235-2239;Ganem, B. Chemtracts: Organic Chemistry (1994) 7(2), 106-107).N-butyl-DNJ has also been tested as an anti-HIV-1 agent in HIV infectedpatients, and is known to be well tolerated. Another alpha glucosidaseinhibitor, deoxynojirimycin (DNJ), has been suggested as an antiviralagent for use in combination with N-(phosphonoacetyl)-L-aspartic acid(PALA) (WO 93/18763). However, combinations ofN-substituted-imino-D-glucitol derivatives and other antiviral agentsfor the treatment of hepatitis virus infections have not been previouslydisclosed or suggested. From results obtained in a woodchuck animalmodel of hepatitis virus infection, Block et al. ((1998) Nature Medicine4(5):610-614) suggested that glucosidase inhibitors such as N-nonyl DNJ,which interfere with specific steps in the N-linked glycosylationpathway of hepatitis virus glycoproteins, may be useful in targetingglycosylation processing as a therapeutic intervention for hepatitis Bvirus.

Compounds such as N-butyl-DNJ (N-butyl-deoxynojirimycin) andN-butyl-DGNJ (N-butyl-desoxynogalactonojirimycin) are reported astreatments of lysosomal storage diseases such as Tay-Sachs disease,Gauchers disease and related ailments. In addition, treatment of cholerahas been reported (U.S. Pat. No. 5,399,567) via inhibition of thesynthesis of glycolipids (U.S. Pat. No. 5,472,969). Inhibition ofglycosyl transferase or glycosidase enzymes that affect the catabolismand metabolism of phopholipids, sphingolipids, cerebrosides,gangliosides by or and within mammalian cells or interference with suchbiochemical processes as attachment to cells, penetration of cellsand/or release from cells. In any event, treatments for these diseasesare badly needed since “With rare exceptions a treatment of these oftenlethal diseases is not possible to date.” (Kolter, T and Sandhoff, K,Inhibitors of Glycosphingolipid Biosynthesis, Chemical Society Reviews,371-381 (1996), WO 98/02161

The use of N-butyl-1,5-dideoxy-1,5-imino-D-glucose and certain otherimino-glucose compounds for the treatment of diseases caused or inducedby human immunodeficincy virus (HIV), cytomeglovirus CMV), hepatitisvirus, respiratory syncytial virus (RSV) and herpes virus (HSV)infection has been reported. Again, treatment of these infections isdesirable and an important public goal.

Nucleoside and Nucleotide Antiviral Agents

Reverse transcriptase inhibitors, including the class of nucleoside andnucleotide analogs, were first developed as drugs for the treatment ofretroviruses such as human immunodeficiency virus (HIV), the causativeagent of AIDS. Increasingly, these compounds have found use againstother viruses, including both RNA and DNA viruses, via viral screeningand chemical modification strategies. Nucleoside and nucleotide analogsexert their antiviral activities by inhibiting the corresponding DNA andRNA polymerases responsible for synthesis of viral DNA and RNA,respectively. Because viruses contain different forms of polymerases,the same nucleoside/nucleotide compound can have a dramaticallydifferent effect against different viruses. For example, lamivudine(3TC) appears to be useful against HBV infection, whereas zidovudine(AZT) appears to have little use against the same virus (Gish, R. G., etal., Exp. Opin. Invest. Drugs (1995) 4(2):95-115).

AZT is an example of a nucleoside/nucleotide analog that can effectglycosylation processes at clinically achievable concentrations ratherthan interfere with DNA replication or protein synthesis (Yan, J.,et.al., J. Biol. Chem., 270, 22836 (1995).

Toxicity has been significant with some nucleoside analog antivirals.For example, clinical tests on the use of the nucleoside analogfialuridine (FIAU) for treatment of chronic hepatitis B were suspendedrecently due to drug-related liver failure leading to death in somepatients. Consequently, there is still a need for safer drug regimensfor the treatment of hepatitis B infections and hepatitis (Mutchnick, M.G., et. al., Antiviral Research (1994) 24:245-257).

Immunomodulators and Inmunostimulants

Immunomodulators/immunostimulators such as interferon alpha and othercytokines have been used for the treatment of HBV infection withpromising results. Unfortunately, the response rates are lower thandesired. Interferon treatment is currently approved by the FDA for thetreatment of Hepatitis B. Other immune system-affecting drug candidatesare presently being investigated. These include thymic peptides for usein the treatment of chronic hepatitis B (CHB), isoprinosine, steroids,Schiff base-forming salicylaldehyde derivatives such as Tucaresol,levamisol, and the like (Gish, R. G., et.al., Exp. Opin. Invest. Drugs(1995) 4(2):95-115; Coates, J. A. V., et.al., Exp. Opin. Ther. Patents(1995) 5(8):747-765).

SUMMARY OF THE INVENTION

As noted above, the use of the substituted-glucamine compounds andderivatives thereof disclosed herein alone, or in combination with otheranti-hepatitis virus compounds has, to the present inventor's knowledge,neither been suggested nor disclosed. The use of two or more anti-viralagents to provide improved therapy for the treatment of hepatitis Bvirus and hepatitis C virus infections is desirable due to the morbidityand mortality of the disease. Combination therapy is also desirablesince it can reduce toxicity in patients as it enables the physician toadminister lower doses of one or more of the drugs being given to apatient. Combination therapy can also help to prevent the development ofdrug resistance in patients (Wiltink, E. H. H., Pharmaceutish WeekbladsScientific Edition (1992) 14(4A):268-274). The result of an improvedefficacy configuration combined with a relative lack of toxicity anddevelopment of resistance would provide a much improved drug treatmentprofile.

Substituted glucamine compounds disclosed herein are effective intreating hepatitis virus infections. Furthermore, the use of thesecompounds in combination with nucleoside or nucleotide antiviralcompounds, or combinations thereof, and/orimmunomodulators/immunostimulants, results in unexpectedly greateranti-hepatitis virus effectiveness of the compounds compared to thecombined antiviral activities expected of the individual compoundsalone. Whether this is due to different mechanisms of action of thedifferent classes of drugs employed or some other biological phenomenonis presently unclear.

Accordingly, in a first aspect, the present invention provides a methodof treating a hepatitis virus infection in a mammal, comprisingadministering to said mammal an anti-hepatitis virus effective amount ofat least one substituted-glucamine compound of Formula I or apharmaceutically acceptable salt thereof:

The compound of Formula I corresponds to the structure:

wherein:

R and R⁵ are independently selected from the group consisting of H,aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl, arylcarbonyloxyalkyl,aminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl,hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl,arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,aryloxyalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, carbonyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonyl, aminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl,heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl,monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, perhaloalkylaralkyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylakenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl,hydroxyalkynyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl,aryloxyalkylcarbonyl, hydroxyalkylcarbonyl, amino(alkyl),alkanoyl(amino)alkyl, (amino)carbonylalkyl, hydroxysulfonealkyl,(amino)carbonylaminoalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl,cycloalkenylcarbonyl, arylcarbonyl, cycloalkenylalkylcarbonyl,cycloalkenylalkenylcarbonyl, cycloalkenylalkynylcarbonyl,bicycloalkenylalkylcarbonyl, tricycloalkenylalkylcarbonyl,tetracycloalkenylalkylcarbonyl, bicycloalkenoxyalkylcarbonyl,tricycloalkenoxyalkylcarbonyl, tetracycloalkenyloxyalkylcarbonyl,cycloalkylalkenylcarbonyl, cycloalkylalkynylcarbonyl, aralkylcarbonyl,aralkoxyalkylcarbonyl, aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylakenylcarbonyl,heteroarylalkynylcarbonyl, aralkoxyalkenylcarbonyl,aryloxyalkynylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl dihydroxyalkylcarbonyl,hydroxyalkenylcarbonyl, dihydroxyalkenylcarbonyl,hydroxyalkynylcarbonyl, haloalkoxyalkenylcarbonyl, andhaloalkoxyalkynylcarbonyl, hydroxysulfonealkylcarbonyl, R⁷ or R⁸,wherein

R⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;

R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³;

R¹ and R⁹ are independently selected from the group consisting of alkyl,aryl, alkenyl, alkynyl, hydrogen or haloalkyl;

R², R³, R⁴, R¹⁰, R¹¹, R¹² and R¹³ are independently selected from thegroup consisting of alkylene, alkenylene, alkynylene or haloalkylene;

X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ and X¹² are independently oxygen, sulfur,sulfoxide or sulfone;

m, n, p, q, r and s are independently 0, 1, 2 or 3;

m+n+p≦3

q+r+s≦3

A, B, C, D and E are independently hydrido, lower alkyl or acyl;

A and B taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

B and C taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

C and D taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

C and E taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

D and E taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring.

In a second aspect, the present invention provides a method for treatinga hepatitis virus infection in a mammal, comprising administering tosaid mammal an antiviral composition consisting essentially of anantiviral effective amount of at least one substituted-glucaminecompound of Formula I as defined above, or a pharmaceutically acceptablesalt thereof. In a third aspect, the present invention provides a methodfor treating a hepatitis virus infection in a mammal, comprisingadministering to said mammal an antiviral composition containing anantiviral effective amount of at least one substituted-glucaminecompound of Formula I , as defined above or a pharmaceuticallyacceptable salt thereof, as above, substantially exclusive of theadministration of any antiviral agent comprising a nucleoside, anucleotide, an immunomodulator, or an immunostimulant.

In a fourth aspect, the present invention provides a method for treatinga hepatitis virus infection in a mammal, consisting essentially ofadministering to said mammal an antiviral composition comprising anantiviral effective amount of at least one substituted-glucaminecompound of Formula I, as defined above, or a pharmaceuticallyacceptable salt thereof, as above. In this method, the antiviralcomposition can consist essentially of an antiviral effective amount ofthe substituted-glucamine compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

In a fifth aspect, the present invention provides a method of treating ahepatitis virus infection in a mammal, comprising administering to saidmammal a first amount of at least one substituted-glucamine compound ofFormula I, as defined above, or a pharmaceutically acceptable saltthereof and a second amount of an antiviral compound selected from thegroup consisting of a nucleoside antiviral compound, a nucleotideantiviral compound, an immunomodulator, an immunostimulant, and mixturesthereof, wherein said first and second amounts of said compoundstogether comprise an anti-hepatitis virus effective amount of saidcompounds.

In a sixth aspect the invention is directed to a method for treating ahepatitis virus infection in a mammal, consisting essentially ofadministering to said mammal an anti-hepatitis virus effective amount ofan antiviral composition consisting essentially of at least oneN-substituted-glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof.

In a seventh aspect, the invention is directed to a method consistingessentially of administering to said mammal an anti-hepatitis viruseffective amount of a composition containing an anti-viral agent, saidanti-viral agent consisting essentially of at least oneN-substituted-glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of treating ahepatitis virus infection in a mammal, comprising administering to saidmammal from about 0.1 mg/kg/day to about 100 mg/kg/day of at least oneN-substituted-glucamine compound of Formula I, as above, and from about0.1 mg/person/day to about 500 mg/person/day of a compound selected fromthe group consisting of a nucleoside antiviral compound, a nucleotideantiviral compound, and a mixture thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition, consisting essentially of an antiviral effective amount ofat least one N-substituted-glucamine compound of Formula I, as definedabove, or a pharmaceutically acceptable salt thereof, as above and apharmaceutically acceptable carrier, excipient, or diluent.

In another aspect, the present invention provides a pharmaceuticalcomposition, containing an antiviral effective amount of at leastsubstituted-glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof, as above, substantially exclusive of anyantiviral agent comprising a nucleoside, a nucleotide, animmunomodulator, or an immunostimulant and a pharmaceutically acceptablecarrier, diluent, or excipient.

In another aspect, the present invention provides a composition,comprising at least substituted-glucamine compound of Formula I, asabove, and an antiviral compound selected from the group consisting of anucleoside antiviral compound, a nucleotide antiviral compound, animmunomodulator, an immunostimulant, and mixtures thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition, comprising a first amount of at least onesubstituted-glucamine compound of Formula I, as above, a second amountof an antiviral compound selected from the group consisting of anucleoside antiviral compound, a nucleotide antiviral compound, animmunomodulator, and immunostimulant, and mixtures thereof, and apharmaceutically acceptable carrier, diluent, or excipient, wherein saidfirst and second amounts of said compounds together comprise anantiviral effective amount of said compounds.

In yet a further aspect, the present invention provides a pharmaceuticalcomposition for treating a hepatitis B virus infection in a mammal,comprising from about 0.1 mg to about 100 mg of at least onesubstituted-glucamine compound of Formula I, as above, and from about0.1 mg to about 500 mg of a compound selected from the group consistingof a nucleoside antiviral compound, a nucleotide antiviral, and mixturesthereof, and a pharmaceutically acceptable carrier, diluent, orexcipient.

Also provided is a pharmaceutical composition for treating a hepatitis Bvirus infection in a human patient, comprising from about 0.1 mg toabout 100 mg of N-(n-nonenyl)-glucamine, from about 0.1 mg to about 500mg of (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate, and apharmaceutically acceptable carrier, diluent, or excipient.

In another aspect, nucleosides and nucleotides and analogs such as AZTthat inhibit sugar processing in addition to or instead of interferingwith DNA or RNA are of special interest for use in combination therapywith iminosugars of this invention and for us in pharmaceuticalformulations with the iminosugars disclosed herein. We intend thatcompounds such as AZT are useful in combination with the iminosugarsdisclosed herein for the treatment of diseases described with regard tothe various aspects of this invention.

Each of the methods of the invention as described hereinabove iseffective for treating various forms of infectious hepatitis. Forms ofhepatitis which can be treated by administration of the above-describedimino sugars include hepatitis B, hepatitis C, hepatitis delta,hepatitis E, hepatitis F and hepatitis G. The methods of the inventionare particularly suited and preferred for the treatment of hepatitis Band hepatitis C.

In another aspect, the present invention provides intermediates usefulfor the preparation of substituted-glucamine compounds or a salt thereofused alone or in combination in the treatment of Hepatitis B infection.

Also provided is a salt, comprising an anti-hepatitis effective amountof an N-substituted-glucamine compound of Formula I, as described above,and a nucleoside having an acidic moiety or a nucleotide.

Also provided is a compound, comprising an N-substituted-glucaminecompound selected from:

The compound of Formula I corresponds to the structure:

wherein:

R is aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl,aryloxyalkynyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkenyl,dihydroxyalkenyl, hydroxyalkynyl, haloalkoxyalkenyl, haloalkoxyalkynyl,alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl,aryloxyalkylcarbonyl, hydroxyalkylcarbonyl, amino(alkyl),alkanoyl(amino)alkyl, (amino)carbonylalkyl, hydroxysulfonealkyl,(amino)carbonylaminoalkyl, or R⁵, wherein

R7=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;

R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³;

R¹ and R⁹ are independently selected from the group consisting of alkyl,aryl, alkenyl, alkynyl, hydrogen or haloalkyl;

R², R³, R⁴, R¹⁰, R¹¹, R¹² and R¹³ are independently selected from thegroup consisting of alkylene, alkenylene, alkynylene or haloalkylene;

X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ and X¹² are independently oxygen, sulfur,sulfoxide or sulfone;

m, n, p, q, r and s are independently 0, 1, 2 or 3;

m+n+p≦3

q+r+s≦3

A, B, C, D and E are independently hydrido, lower alkyl or acyl;

A and B taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

B and C taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

C and D taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

C and E taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

D and E taken together with the atoms to which they are attached mayform a five or six membered heterocyclic ring;

wherein the main chain in R or R⁵ contains between one and twenty atoms;

the main chain of each of R⁷ and R⁸ contains between four and twentyatoms and either of R¹X¹ or R⁹X⁹;

provided that R and R⁵ are not both hydrido.

Further scope of the present invention will become apparent from thedetailed description and drawings provided below. However, it should beunderstood that the following detailed description and examples, whileindicating preferred embodiments of the invention, are given by way ofillustration only since various changes and modifications within thespirit and scope of the invention will become apparent to those skilledin the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects, features, and advantages of the presentinvention will be better understood from the following detaileddescription taken in conjunction with the accompanying drawings, all ofwhich are given by way of illustration only, and are not limitative ofthe present invention, in which:

FIG. 1 shows the anti-hepatitis B virus activity of(−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC) alone and incombination with N-nonyl-DNJ in vitro.

FIG. 2 shows the plasma concentration of N-nonyl-DNJ versus dose ofN-nonyl-DNJ for each animal in Example 5, from samples taken duringdosing. Animals are indicated by unique letters, and a small amount ofrandom noise has been added to the dose value so that overlapping valuescan be distinguished.

FIG. 3 shows the slope of Log(IPDNA +10) to week versus dose. A distinctletter is used for each animal. The fitted line is from a four parameterlogistic model. The parameters of the fitted curve and their approximatestandard errors are shown on the plot.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is provided to aid those skilled inthe art in practicing the present invention. Even so, this detaileddescription should not be construed to unduly limit the presentinvention as modifications and variations in the embodiments discussedherein can be made by those of ordinary skill in the art withoutdeparting from the spirit or scope of the present inventive discovery.

The contents of each of the patent documents and other references citedherein, including the contents of the references cited within theseprimary references, are herein incorporated by reference in theirentirety.

It has been discovered that the use of substituted-glucamine compoundsis effective when such compounds are used alone for treating hepatitisvirus infections. In accordance with the present invention, it hasadditionally been discovered that combinations of substituted-glucaminecompounds with anti-hepatitis virus nucleosides or nucleotides, and/orimmunomodulators/immunostimulants, are also effective for this purpose.There is some evidence that certain combinations may be more effectivein inhibiting hepatitis virus replication than would have been expectedvia the combined use of the individual compounds.

The present invention thus provides pharmaceutical compositions andmethods of treating hepatitis virus infections, especially hepatitis Band C virus infections, in humans, other mammals, and cells usingsubstituted-glucamine compounds alone or in combination with either anantiviral nucleoside, an antiviral nucleotide, mixtures thereof, and/oran immunomodulating or immunostimulating agent. Thesubstituted-glucamine compounds may have basic nitrogen atoms and may beused in the form of a pharmaceutically acceptable salt. Nucleosides andnucleotides useful in the present invention are substituted purine orpyrimidine heterocycles further substituted with R¹ in Formulas II-VI atthe 9 position in the case of purines or with R¹ at the 1 position inthe case of pyrimidines. The immunomodulating and immunostimulatingagents useful in the present invention include those that stimulateimmune responses effective in controlling or eliminating viruses orother infectious agents. Non-limiting examples of such immunomodulatingand immunostimulating agents include cytokines, peptide agonists,steroids, and classic drugs such as levamisol. The drug combinations ofthis invention may be provided to a cell or cells, or to a human orother mammalian patient, either in separate pharmaceutically acceptableformulations administered simultaneously or sequentially, formulationscontaining more than one therapeutic agent, or by an assortment ofsingle agent and multiple agent formulations. However administered,these drug combinations form an anti-hepatitis virus effective amount ofcomponents.

As used herein, the term “anti-hepatitis-virus effective amount” refersto an amount of an N-substituted-glucamine compound alone, or a combinedamount of (1) an N-substituted-glucamine compound with either anantiviral nucleoside, an antiviral nucleotide, a mixture of an antiviralnucleoside and an antiviral nucleotide, or animmunomodulating/-immunostimulating agent (or mixtures thereof), or (2)a combined amount of an N-substituted-glucamine compound with anantiviral nucleoside, an antiviral nucleotide, or a mixture thereof, andan immunomodulating/-immunostimulating agent (or mixtures thereof)effective in treating hepatitis virus infection. The antiviraleffectiveness of the aforementioned combinations may involve a varietyof different phenomena associated with viral replication and assembly.These may include, for example, blocking hepatitis viral DNA synthesis;blocking viral transcription; blocking virion assembly; blocking virionrelease or secretion from infected cells; blocking or altering viralprotein function, including the function of viral envelope protein(s);and/or the production of immature or otherwise non-functional virions.The overall effect is an inhibition of viral replication and infectionof additional cells, and therefore inhibition of the progress ofinfection in the patient.

Substituted-Glucamine Compounds

Substituted-glucamine compounds useful in the present invention arerepresented by structure Formula I above or salts thereof.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 to andincluding 20 carbon atoms. Substituted alkyl, alone or in combination,means an alkyl radical which is optionally substituted as defined hereinwith respect to the definitions of aryl and heterocyclo. Alkylene meansa saturated aliphatic hydrocarbyl attached at two or more positions suchas methylene (—CH₂—). Examples of alkyl radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,iso-amyl, hexyl, octyl, noyl and the like.

The term “lower alkyl”, alone or in combination, means alkyl containingfrom 1 to and including 6 carbon atoms.

The phrase “in the main chain” means the longest contiguous or adjacentchain of carbon atoms starting at the point of attachment of a group tothe compounds of this invention.

The phrase “linear chain of atoms” means the longest straight chain ofatoms independently selected from carbon, nitrogen, oxygen and sulfur.

The term “hydrido” means a hydrogen substituent, i.e., —H.

The term “alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds andcontaining from 2 to 20 carbon atoms. Substituted alkenyl, alone or incombination, means an alkyl radical which is optionally substituted asdefined herein with respect to the definitions of aryl and heterocyclo.Alkenylene means a carbon-carbon double bond system attached at two ormore positions such as ethenylene [(—CH═CH—),(—C::C—)]. Examples ofsuitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl,1,4-butadienyl and the like.

The term lower “alkenyl”, alone or in combination, means alkylcontaining from 1 to and including 6 carbon atoms.

The term “alkynyl”, alone or in combination, means a straight-chain orbranched chain hydrocarbon radical having one or more triple bonds andcontaining preferably from 2 to 20 carbon atoms. Substituted alkynyl,alone or in combination, means an alkyl radical which is optionallysubstituted as defined herein with respect to the definitions of aryland heterocyclo. Alkynylene means a carbon-carbon triple bond attachedat two positions such as ethynylene (—C:::C—). Examples of alkynylradicals include ethynyl, propynyl (propargyl), butynyl and the like.

The term lower “alkynyl”, alone or in combination, means alkylcontaining from 1 to and including 6 carbon atoms.

The term “alkoxy”, alone or in combination, means an alkyl ether radicalwherein the term alkyl is as defined above. Examples of suitable alkylether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, ethoxyethoxy, methoxypropoxyethoxy,ethoxypentoxyethoxyethoxy and the like.

The term “cycloalkyl”, alone or in combination, means a saturated orpartially saturated monocyclic, bicyclic or tricyclic alkyl radicalwherein each cyclic moiety contains preferably from 3 to 10 carbon atomring members and which may optionally be a benzo fused ring system whichis optionally substituted as defined herein with respect to thedefinition of aryl. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.“Bicyclic” and “tricyclic” as used herein are intended to include bothfused ring systems, such as decahydonapthalene, octahydronapthalene aswell as the multicyclic (multicentered) saturated or partiallyunsaturated type. The latter type of isomer is exemplified in general bybicyclo[2,2,2]octane, bicyclo[2,2,2]octane, bicyclo[1,1,1]pentane,camphor and bicyclo[3,2,1]octane.

The term “cycloalkylalkyl” means an alkyl radical as defined above whichis substituted by a cycloalkyl radical as defined above. Examples ofsuch cycloalkylalkyl radicals include cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl,2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyland the like.

The terms “benzo” or “benz”, alone or in combination, means the divalentradical C₆H₄═ derived from benzene. Examples include benzothiophene andbenzimidazole.

The term “aryl”, alone or in combination, or “ara” or” “ar” incombination, means a phenyl (—Ø) or naphthyl radical which is optionallysubstituted with one or more substituents selected from the groupconsisting of alkyl, alkylcarbonyl, alkoxy, halogen, hydroxy, amino,nitro, cyano, haloalkyl, haloalkylthio, haloalkyloxy, carboxy,alkoxycarbonyl, cycloalkyl, heterocyclo, alkylcarbonylamino,aminoalkanoyl, amido, aminocarbonyl, arylcarbonyl, arylcarbonylamino,aryl, aryloxy, alkyloxycarbonyl, arylalkyloxycarbonyl,alkoxycarbonylamino, disubstituted amino, aminocarbonyl, disubstitutedaminocarbonyl, amido, disubstitutedamido, aralkoxycarbonylamino,alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkylthio,haloalkylsulfinyl, haloalkylsulfonyl, arylthio, arylsulfinyl,arylsulfonyl, alkylsulfinylamino, alkylsulfonylamino,haloalkylsulfinylamino, haloalkylsulfonylamino, arylsulfinylamino,arylsulfonylamino, heterocyclo, sulfonate, sulfonic acid,trisubstitutedsilyl and the like. Examples of aryl radicals are phenyl,p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,3-methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl,3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl,2-methyl-3-acetamidophenyl, 4-CF₃-phenyl, 2-methyl-3-aminophenyl,4-CF₃O-phenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and thelike.

The terms “aralkyl” and “aralkoxy”, alone or in combination, means analkyl or alkoxy radical as defined above in which at least one hydrogenatom is replaced by an aryl radical as defined above. Thus, “aryl”includes substituents such as benzyl, 2-phenylethyl, dibenzylmethyl,hydroxyphenylmethyl, methylphenylmethyl, and diphenylmethyl, and“aryloxy” includes substituents such as benzyloxy, diphenylmethoxy,4-methoxyphenylmethoxy and the like.

The term “aralkoxycarbonyl”, alone or in combination, means a radical ofthe formula aralkyl-O-C(O)— in which the term “aralkyl” has thesignificance given above. Examples of an aralkoxycarbonyl radical arebenzyloxycarbonyl (Z) and 4-methoxyphenylmethoxycarbonyl (MOS).

The term “aryloxy” means a radical of the formula aryl-O— in which theterm aryl has the significance given above.

The term “alkanoyl”, alone or in combination, means an acyl radicalderived from an alkanecarboxylic acid, examples of which include acetyl,propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.

The term “alkylcarbonyl” (alkyl-(C═O)— means alkanoyl.

The term “cycloalkylcarbonyl” means an acyl radical of the formulacycloalkyl-(C═O)— in which the term “cycloalkyl” has the significancegive above, such as cyclopropylcarbonyl, cyclohexylcarbonyl,adamantylcarbonyl, 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,1-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like.

The term “aralkanoyl” means an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, phenylacetyl,3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like. The term “aroyl” means an acyl radical derived from anarylcarboxylic acid, “aryl”, having the meaning given above. Examples ofsuch aroyl radicals include substituted and unsubstituted benzoyl ornapthoyl such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like.

The term “arylcarbonyl” is aroyl.

Where substituents are recited without qualification as to substitution,both substituted and unsubstituted forms are encompassed. Where asubstituent is qualified as “substituted,” the substituted form isspecifically intended.

The term “substituted”, when used in combination and not otherwisedefined in this paragraph, means one to four substituents attached thatare independently selected from the group comprising alkyl,alkylcarbonyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, thiol,haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo,alkanoylamino, aminoalkanoyl, amido, aminocarbonyl, arylcarbonyl, aryl,aryloxy, alkyloxycarbonyl, arylalkyloxycarbonyl, alkoxycarbonylamino,amino, disubstituted amino, substituted aminocarbonyl, disubstitutedaminocarbonyl, substituted amido, disubstitutedamido,aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,arylthio, arylsulfinyl, arylsulfonyl, heterocyclo, sulfonate, sulfonicacid and trisubstitutedsilyl.

The term “carbonyl”, alone includes formyl [—(C═O)—H] and in combinationis a —C═O— group.

The term “oxo” means the double bonded oxygen.

The term “thiocarbonyl”, alone includes thioformyl [—(C═S)—H] and incombination is a —C═S— group.

The term “oxy” or “oxa” means a —O— group.

The term “carboxy” is —COOH or the corresponding “carboxylate” anionsuch as is in a carboxylic acid salt. The term “heterocyclo,” alone orin combination, means a saturated or partially unsaturated monocyclic,bicyclic or tricyclic heterocycle radical containing at least one,preferably 1 to 4, more preferably 1 to 2, nitrogen, oxygen or sulfuratom ring members and having preferably 3 to 8 ring members in eachring, more preferably 3 to 7 ring members in each ring and mostpreferably 5 to 6 ring members in each ring. “Heterocyclo” is intendedto include sulfones, sulfoxides, N-oxides of tertiary nitrogen ringmembers, and carbocyclic fused and benzo fused ring systems. Suchheterocyclo radicals may be optionally substituted on at least one,preferably 1 to 4, more preferably 1 to 2, carbon atoms by halogen,alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl, heteroaryl, heteroaralkyl,amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and thelike, and/or on a secondary nitrogen atom (i.e., —NH—) by hydroxy,alkyl, aralkoxycarbonyl, alkanoyl, heteroaralkyl, phenyl or phenylalkyl,and/or on a tertiary nitrogen atom (i.e., ═N—) by oxido.

The term “heterocycloalkyl” means an alkyl radical as defined above inwhich at least one hydrogen atom is replaced by a heterocyclo radical asdefined above, such as pyrrolidinylmethyl, tetrahydrothienylmethyl,pyridylmethyl and the like.

The term “heteroaryl”, alone or in combination, means an aromaticheterocyclo radical as defined above, which is optionally substituted asdefined above with respect to the definitions of aryl and heterocyclo.Examples of such heterocyclo and heteroaryl groups are pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl,imidazolyl (e.g., imidazol 4-yl, 1-benzyloxycarbonylimidazol-4-yl,etc.), pyrazolyl, pyridyl, (e.g., 2-(1-piperidinyl)pyridyl and2-(4-benzyl piperazin-1-yl-1-pyridinyl, etc.), pyrazinyl, pyrimidinyl,furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl and its sulfoxide andsulfone derivatives, triazolyl, oxazolyl, thiazolyl, indolyl (e.g.,2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-,2-,4- or 5-benzimidazolyl,methylenedioxyphen-4-yl, methylenedioxyphen-5-yl, ethylenedioxyphenyl,benzothiazolyl, benzopyranyl, benzofuryl, 2,3-dihydrobenzofuryl,benzoxazolyl, thiopheneyl and the like.

The term “cycloalkylalkoxycarbonyl” means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O—COOHwherein cycloalkylalkyl has the meaning given above.

The term “aryloxyalkanoyl” means an acyl radical of the formulaaryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.

The term “heterocycloalkoxycarbonyl”, means an acyl group derived fromheterocycloalkyl-O—COOH wherein heterocycloalkyl is as defined above.

The term “heterocycloalkanoyl” is an acyl radical derived from aheterocycloalkylcarboxylic acid wherein heterocyclo has the meaninggiven above.

The term “heterocycloalkanoyl” is an acyl radical derived from aheterocycloalkylcarboxylic acid wherein heterocyclo has the meaninggiven above.

The term “heterocycloalkoxycarbonyl” means an acyl radical derived froma heterocycloalkyl-O—COOH wherein heterocyclo has the meaning givenabove.

The term “heteroaryloxycarbonyl” means an acyl radical derived from acarboxylic acid represented by heteroaryl-O—COOH wherein heteroaryl hasthe meaning given above.

The term “trisubstitutedsilyl”, alone or in combination, means asilicone group substituted at its three free valences with groups aslisted herein under the definition of substituted amino. Examplesinclude trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and thelike.

The terms “sulfonate”, “sulfonic acid” and “sulfonic”, alone or incombination, mean the —SO₃H group and its anion as the sulfonic acid isused in salt formation.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like.

The term “amido”, alone or in combination, means the product of thecombination of a carboxylic acid with an amine as defined herein.

The term “amino”, alone or in combination, means an —N═group wherein theamino group can be a primary, secondary or tertiary amino groupcontaining substituents selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like. Primary amino has two freevalences as hydrogen, i.e., —NH₂. Secondary amino, which is alsomono-substituted amino or N-substituted amino, has one free valencesubstituted as above. Tertiary amino, which is also disubstituted aminoor N,N-disubstituted amino, has two free valences substituted as above.For example, —NH₂ is unsubstituted amino, —N(H)(CH₃) is mono-substitutedamino (N-methylamino) and —N(CH3)(CH₂phenyl).is disubstituted amino(N-methyl-N-benzylamino).

The term “aminoalkanoyl” means an acyl group derived from anamino-substituted alkylcarboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “haloalkyl”, alone or in combination, means an alkyl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen. Haloalkylene means a halohydrocarbyl groupattached at two or more positions. Examples include fluoromethylene(—CFH—), difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and thelike. Examples of such haloalkyl radicals include chloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,1,1,1-trifluoroethyl, perfluorodecyl and the like.

The term “lowerhaloalkyl”, alone or in combination, means haloalkylcontaining from 1 to and including 6 carbon atoms.

The terms “thia” and “thio”, alone or in combination, mean a —S— groupor an ether wherein the oxygen is replaced with a sulfur. The oxidizedderivatives of the thio function are included. Examples includealkylthia groups such as methylthia and oxidation products such as thesulfoxide [—(S—O)—]and sulfone [—(S—O₂)—] derivatives.

The term “thiol” means an —SH group.

The term “leaving group” (L or W) generally refers to groups readilydisplaceable by a nucleophile, such as an amine, a thiol or an alcoholnucleophile. Such leaving groups are well known in the art. Examples ofsuch leaving groups include, but are not limited to,N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,tosylates and the like. Preferred leaving groups are indicated hereinwhere appropriate. The definitions above apply except where arespecified otherwise. For example, monohaloalkyl specifically means analkyl group with one halogen substituent. Compounds disclosed herein arethose expected to be sufficiently stable to be used as presented hereinor to be used in the preparation of the materials shown herein. Thisspecifically includes temporary or transient intermediates in chemicalreactions and compounds that may exist in different forms depending upontheir environment. It is well known in the art that stability ispartially defined in relation to use. For illustration, aldehydes may behydrated when in an aqueous system but not hydrated in a non-aqueoussystem and various solvates may be used in pharmaceutical compositionsrather than an anhydrous compound. The pharmaceutical chloral is amaterial wherein the soporific is conveniently administered as thehydrate (chloral hydrate) whereas the anhydrous form(trichloroacetaldehyde) is conveniently used (or made in situ) as areagent or substrate in synthetic reactions such Wittig reactions.

The present invention comprises any tautomeric forms of compounds ofFormula I. The present invention also comprises compounds of Formula Ihaving one or more asymmetric carbons. It is known to those skilled inthe art that those imino sugars of the present invention havingasymmetric carbon atoms may exist in diastereomeric, racemic, oroptically active forms. All of these forms are contemplated within thescope of this invention. More specifically, the present inventionincludes enantiomers, diastereomers, racemic mixtures, and othermixtures thereof.

Representative glucamine compounds useful in the present inventioninclude, but are not limited to compounds in the Tables:

TABLE 1

R  1.

 2.

 3.

 4.

 5.

 6.

 7.

 8.

 9.

10.

11.

12.

13.

14.

15.

16.

TABLE 2

R  1. —(CH₂)₁₁CF₃  2. —(CH₂)₇O(CH₂)₂OCH₂CF₃  3. —(CH₂)₄O(CH₂)₄CF₃  4.

 5.

 6.

 7.

 8.

 9.

10.

11.

12. —(CF₂)₇CF₃ 13. —(CH₂)₇O(CF₂)₇CF₃ 14. —CF₂CH₂O(CH₂)₃SCF₃ 15.—(CH₂)₄S(CH₂)₄CF₃ 16. —(CH₂)₇S(CH₂)₂SCF₃ 17. —(CH₂)₇S(CH₂)₂SCH₂CF₃ 18.

19.

20.

21.

22.

TABLE 3

R  1. —(CH₂)₂O(CH₂)₆CF₃  2. —(CH₂)₆O(CH₂)₂CF₃  3.—(CH₂)₂O(CH₂)₂O(CH₂)₂OCF₃  4. —(CH₂)₆O(CH₂)₂O(CH₂)₂OCF₃  5.—(CH₂)₂O(CH₂)₂O(CH₂)₃CF₃  6. —(CH₂)₂O(CH₂)₂O(CH₂)₂CF₃  7.

 8.

 9. —(CH₂)₆S(CH₂)₂CF₃ 10. —(CH₂)₄S(CH₂)₂CF₃ 11. —(CH₂)₂S(CF₂)₆CF₃ 12.—CH₂(CHOH)CH₂(CHNH₂)(CH₂)₁₂CH₃ 13. —(CH₂)₂O(CF₂)₂O(CH₂)₂OCF₃ 14.—(CH₂)₆S(CH₂)₂O(CH₂)₂OCF₃ 15. —(CH₂)₂O(CH₂)₂O(CH₂)₂CF₂CF₃ 16.—(CH₂)₂O(CH₂)₂S(CH₂)₂CF₃ 17.

18.

19. —(CH₂)₆S(CH₂)₂SO₂CF₃ 20. —(CH₂)₄O(CH₂)₂SO₂CF₃

TABLE 4

R  1. —(CH₂)₂O(CH₂)₆CF₃  2. —(CH₂)₆O(CH₂)₂CF₃  3.—(CH₂)₂O(CH₂)₂O(CH₂)₂OCF₃  4. —(CH₂)₆O(CH₂)₂O(CH₂)₂OCF₃  5.—(CH₂)₂O(CH₂)₂O(CH₂)₃CF₃  6. —(CH₂)₂O(CH₂)₂O(CH₂)₂CF₃  7.

 8.

 9. —(CH₂)₆S(CH₂)₂CF₃ 10. —(CH₂)₄S(CH₂)₂CF₃ 11. —(CH₂)₂S(CF₂)₆CF₃ 12.—CH₂(CHOH)CH₂(CHNH₂)(CH₂)₁₂CH₃ 13. —(CH₂)₂O(CF₂)₂O(CH₂)₂OCF₃ 14.—(CH₂)₆S(CH₂)₂O(CH₂)₂OCF₃ 15. —(CH₂)₂O(CH₂)₂O(CH₂)₂CF₂CF₃ 16.—(CH₂)₂O(CH₂)₂S(CH₂)₂CF₃ 17.

18.

19. —(CH₂)₆S(CH₂)₂SO₂CF₃ 20. —(CH₂)₄O(CH₂)₂SO₂CF₃

TABLE 5

R  1.

 2.

 3.

 4.

 5.

 6.

 7.

 8.

 9. —(CH₂)₈CF₃ 10. —(CH₂)₇CF₃ 11. —(CH₂)₉CF₃ 12. —(CH₂)₈CH₃ 13.—(CH₂)₉CH₃ 14.

15.

16.

17.

18.

19.

20.

21.

22. —(CH₂)₈SO₂CF₃ 23. —(CH₂NH(CH₂)₄SO₂CF₃ 24. —(CH₂)₉NHSO₂CF₃ 25.—(CH₂)₈SO₂NHC₆H₅ 26.

TABLE 6

R  1.

 2.

 3.

 4.

 5.

 6.

 7.

 8.

 9. —(CH₂)₈CF₃ 10. —(CH₂)₇CF₃ 11. —(CH₂)₉CF₃ 12. —(CH₂)₈CH₃ 13.—(CH₂)₉CH₃ 14.

15.

16.

17.

18.

19.

20.

21.

22. —(CH₂)₈SO₂CF₃ 23. —(CH₂NH(CH₂)₄SO₂CF₃ 24. —(CH₂)₉NHSO₂CF₃ 25.—(CH₂)₈SO₂NHC₆H₅ 26.

TABLE 7

R  1. —(CH₂)₁₁CF₃  2. —(CH₂)₇O(CH₂)₂OCH₂CF₃  3. —(CH₂)₄O(CH₂)₄CF₃  4.

 5.

 6.

 7.

 8.

 9.

10.

11.

12. —(CF₂)₇CF₃ 13. —(CH₂)₇O(CF₂)₇CF₃ 14. —CF₂CH₂O(CH₂)₃SCF₃ 15.—(CH₂)₄S(CH₂)₄CF₃ 16. —(CH₂)₇S(CH₂)₂SCF₃ 17. —(CH₂)₇S(CH₂)₂SCH₂CF₃ 18.

19.

20.

21.

22.

TABLE 8

R  1.

 2.

 3.

 4.

 5.

 6.

 7.

 8.

 9.

10.

11.

12.

13.

14.

15.

16.

Among the substituents that may constitute R and/or R⁵ in the compoundsof Formula I, certain classes are preferred. A class of R/R⁵substituents which includes compounds of anti-hepatitis efficacy andcompounds useful as intermediates in preparing therapeutic glucamines isthe following:

TABLE 9 aryloxyalkoxyalkyl, haloalkylcarbonyl, alkylcarbonyloxyalkyl,hydroxyalkylcarbonyl, arylcarbonyloxyalkyl, haloalkyloxyalkylcarbonyl,alkylcarbonylaminoalkyl, cycloalkyl, arylcarbonylaminoalkyl,cycloalkyloxyalkylcarbonyl, alkoxycarbonylaminoalkyl,alkoxyalkylcarbonyl, aminocarbonylaminoalkyl, cycloalkylalkylcarbonyl,aminothiocarbonylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkoxyalkyl,hydroxyalkyl, aryloxyalkoxyalkylcarbonyl, carboxyalkyl,alkylcarbonyloxyalkylcarbonyl, alkoxycarbonylalkyl,arylcarbonyloxyalkylcarbonyl, aminocarbonylalkyl, aminoalkylcarbonyl,aminothiocarbonylalkyl, alkylcarbonylaminoalkylcarbonylaminosulfonealkyl, heterocycloalkyl, arylcarbonylaminoalkylcarbonyl,heteroaryloxyalkyl, alkoxycarbonylaminoalkyl- heteroarylthiaalkyl,carbonyl heterocyclooxyalkyl, aminocarbonylaminoalkylcarbonylheterocyclothiaalkyl, arylthiaalkyl, haloalkyl,aminothiocarbonylaminoalkylcar- haloalkyloxyalkyl, carbonyl, bonyl,arylalkenylcarbonyl, cycloalkyloxyalkyl, carboxyalkylcarbonyl,cycloalkylalkyloxyalkyl, alkoxycarbonylalkylcarbonyl, alkenylcarbonyl,aminocarbonylalkylcarbonyl, alkynylcarbonyl,aminothiocarbonylalkylcarbonyl, arylalkylcarbonyl,aminosulfonealkylcarbonyl, aryloxyalkyl, arylalkynylcarbonyl,aryloxyalkylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkylalkyloxyalkyl- carbonyl

Provided that not both of R and R⁵ are hydrido, the glucamine compoundsof Formula I comprising the substituents of Table 9 are believed to benovel compounds.

Another group of glucamine compounds believed to be novel are those inwhich both R and R⁵ are selected from the following:

TABLE 10 alkyl, aminoalkyl, arylalkylcarbonyl, arylcarbonylaminoalkyl,aryloxyalkylcarbonyl, alkenyl, alkynyl, haloalkylcarbonyl, alkoxyalkyl,hydroxyalkyl, hydroxyalkylcarbonyl, arylalkyl, arylalkenyl,haloalkyloxyalkylcarbonyl, arylalkynyl, cycloalkyl, heterocycloalkyl,cycloalkyloxyalkylcarbonyl, heteroarylalkyl, alkoxyalkylcarbonyl,heteroaryloxyalkyl, cycloalkylalkylcarbonyl, heteroarylthiaalkyl,alkoxycarbonyl, heterocyclooxyalkyl, alkylcarbonyl,heterocyclothiaalkyl, aryloxyalkoxyalkylcarbonyl, arylthiaalkyl,haloalkyl, alkylcarbonyloxyalkylcarbonyl, haloalkyloxyalkyl,cycloalkyloxyalkyl, arylcarbonyloxyalkylcarbonyl,cycloalkylalkyloxyalkyl, aminoalkylcarbonyl, alkenylcarbonyl,alkylcarbonylaminoalkyl alkynylcarbonyl, carbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkyl- carbonyl,aminocarbonylaminoalkyl- carbonyl aminothiocarbonylaminoalkylcar- bonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl,heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl,monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl

Where either or both of R or R⁵ is lower alkyl, R and R⁵ are preferablynot the same.

Other preferred glucamine compounds of this invention are those in whichR is selected from the following substituents:

TABLE 11A aryloxyalkoxyalkyl, aminoalkyl, alkylcarbonyloxyalkyl, alkyl,alkylcarbonylaminoalkyl, arylcarbonyloxyalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, alkylcarbonyloxyalkylcarbonyl,aminocarbonylaminoalkyl, arylcarbonyloxyalkylcarbonyl,aminothiocarbonylaminoalkyl, aminoalkylcarbonyl, alkenyl, alkynyl,alkoxyalkyl, alkylcarbonylaminoalkyl hydroxyalkyl, arylalkyl, carbonylarylalkenyl, carboxyalkyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl- aminocarbonylalkyl,carbonyl aminothiocarbonylalkyl, aminocarbonylaminoalkylcarbonylaminosulfonealkyl, arylalkynyl, heterocycloalkyl,aminothiocarbonylaminoalkylcar- heteroarylalkyl, bonyl,arylalkenylcarbonyl, heteroaryloxyalkyl, carboxyalkylcarbonyl,heteroarylthiaalkyl, alkoxycarbonylalkylcarbonyl, heterocyclcooxyalkyl,aminocarbonylalkylcarbonyl, heterocyclothiaalkyl,aminothiocarbonylalkylcarbonyl, aryloxyalkyl, arylthiaalkyl,aminosulfonealkylcarbonyl, haloalkyl, haloalkyloxyalkyl,arylalkynylcarbonyl, carbonyl, cycloalkyloxyalkyl,heterocycloalkylcarbonyl, cycloalkylalkyloxyalkyl, heteroarylalkyl,alkenylcarbonyl, heteroaryloxyalkyl, alkynylcarbonyl,heteroarylthiaalkylcarbonyl, arylalkylcarbonyl,heterocyclooxyalkylcarbonyl, aryloxyalkyl, heterocyclothiaalkylcarbonyl,aryloxyalkylcarbonyl, arylthiaalkylcarbonyl, substitutedmonohaloalkylcarbonyl, aryloxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,haloalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl hydroxyalkylcarbonyl,haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl,alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, alkoxycarbonyl,substituted alkylcarbonyl, aryloxyalkoxyalkylcarbonyl,

and R⁵ is selected from the following:

TABLE 11B H, alkyl, alkenyl, alkynyl, alkoxyalkyl, arylalkyl,aryloxyalkyl, cycloalkyl, cycloalkylalkyl, aryloxyalkyl, haloalkyl,hydroxyalkyl, haloalkyloxyalkyl, cycloalkyloxyalkylcycloalkylalkyloxyalkyl

Additional groups of preferred R and/or R⁵ substituents include thefollowing:

(a) alkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, arylalkyl,arylalkenyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, haloalkyl,haloalkyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,cycloalkenylalkyl, cycloalkylalkenyl, cycloalkylalkynyl,heterocycloalkenyl, heteroarylalkenyl, heteroarylalkynyl, hydroxyalkyl,haloalkoxyalkenyl, and haloalkoxyalkynyl;

(b) aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl,alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, carboxyalkyl, aminocarbonylalkyl,aminothiocarbonylalkyl, aminosulfonealkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,aryloxyalkyl, arylthiaalkyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl,aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl,aralkenoxyalkenyl, aryloxyalkenyl, aryloxyalkynyl, hydroxyalkenyl, andhydroxyalkynyl;

(c) alkyl, alkenyl, alkynyl, alkoxyalkyl, arylalkyl, heterocycloalkyl,heteroarylalkyl, haloalkyl, haloalkyloxyalkyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, heterocycloalkenyl,heteroarylalkenyl, haloalkoxyalkenyl, and haloalkoxyalkynyl;

(d) aryloxyalkoxyalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,aminocarbonylaminoalkyl, carboxyalkyl, aminocarbonylalkyl,aminosulfonealkyl, heteroaryloxyalkyl, heteroarylthiaalkyl,heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, aralkoxyalkyl,aralkenoxyalkyl, and aryloxyalkenyl;

(e) aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,alkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkoxyalkylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, aminocarbonylalkylcarbonyl,aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl,arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl,heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,aryloxyalkylcarbonyl, arylthiaalkylcarbonyl, carbonyl,haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkenylcarbonyl,arylcarbonyl, cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl,aryloxyalkynylcarbonyl, hydroxyalkylcarbonyl, hydroxyalkenylcarbonyl,hydroxyalkynylcarbonyl, haloalkoxyalkenylcarbonyl, andhaloalkoxyalkynylcarbonyl;

(f) alkylcarbonyl, aminoalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkoxyalkylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl,haloalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl,cycloalkenylalkylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, heterocycloalkenylcarbonyl,heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl,hydroxyalkylcarbonyl, haloalkoxyalkenylcarbonyl, andhaloalkoxyalkynylcarbonyl;

(g) aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl,carboxyalkylcarbonyl, aminocarbonylalkylcarbonyl,aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl,heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,aryloxyalkylcarbonyl, arylthiaalkylcarbonyl, cycloalkyloxyalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,aryloxyalkenylcarbonyl, aryloxyalkynylcarbonyl, hydroxyalkenylcarbonyl,and hydroxyalkynylcarbonyl;

(h) alkylcarbonyl, carbonyl, alkenylcarbonyl, alkynylcarbonyl,alkoxyalkylcarbonyl, arylalkylcarbonyl, heterocycloalkylcarbonyl,heteroarylalkylcarbonyl, haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkenylcarbonyl,arylcarbonyl, heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,haloalkoxyalkenylcarbonyl, and haloalkoxyalkynylcarbonyl; and

(i) aryloxyalkoxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,carboxyalkylcarbonyl, aminocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, heteroaryloxyalkylcarbonyl,heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl,heterocyclothiaalkylcarbonyl, aryloxyalkylcarbonyl,arylthiaalkylcarbonyl, cycloalkyloxyalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, aralkoxyalkylcarbonyl,aralkenoxyalkylcarbonyl, and aryloxyalkenylcarbonyl.

Other preferred classes of R/R⁵ substituents are those described asconstituting the N-substituent of a 1,5-dideoxy-1,5-amino-D-glucitolcompound in copending Ser. No. 09/503,945, filed Feb. 14, 2000 as alsoset forth hereinbelow. For example, to provide a compound, which in itsfree base form, is relatively strongly alkaline, it is advantageous forat least one of R and R⁵to be selected from among:

TABLE 12 aryloxyalkoxyalkyl arylcarbonylaminoalkyl alkylcarbonyloxyalkylalkoxycarbonylamino- substituted alkyl alkyl arylcarbonyloxyalkylaminocarbonylaminoalkyl aminoalkyl aminothiocarbonyl-alkylcarbonylamino- aminoalkyl alkyl alkenyl arylalkenyl carboxyalkylalkoxycarbonylalkyl aminocarbonylalkyl aminothiocarbonylalkylaryloxyalkyl aminosulfonealkyl arylthiaalkyl arylalkynyl monohaloalkylheterocycloalkyl haloalkyloxyalkyl heteroarylalkyl cycloalkyloxyalkylheteroaryloxyalkyl cycloalkylalkyloxyalkyl heteroarylthiaalkylheterocyclooxyalkyl heterocyclothiaalkyl

Salts of such compounds with strong pharmaceutically acceptable acidsprovide highly dissociable compounds that are effective in the method ofthe invention. Although the primary glucamine is also alkaline, it isgenerally preferred that at least one of R and R⁵ not be hydrogen. Morepreferably, R and/or R⁵may be selected from among: substituted aryl,arylcarbonylaminoalkyl, aminocarbonylaminoalkyl, alkenyl, arylalkenyl,arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,heterocyclooxyalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyloxyalkyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl and perhaloalkylaralkyl; ofwhich substituted alkyl, alkenyl, arylalkenyl, heterocycloalkyl,heteroarylalkyl, heteroaryloxyalkyl, heterocyclooxyalkyl, aryloxyalkyl,haloalkyloxyalkyl and perhaloalkylaralkyl are particularly preferred,and alkenyl, arylalkenyl, heterocycloalkyl, heteroarylalkyl,aryloxyalkyl haloalkyloxyalkyl, perhaloalkylaralkyl andcycloalkyloxyalkyl.

However, amidoglucamine compounds of Formula I and pharmaceuticallyacceptable salts thereof are also useful in the treatment of hepatitisinfections, or alternatively in the synthesis of other compounds ofFormula I that are effective for such treatment. Thus, members of thefollowing group of amido and other substituents may also serveeffectively as the R or R⁵ substituent or both in the compounds ofFormula I:

TABLE 13 carbonyl carbonyl alkenylcarbonyl alkoxycarbonylamino-alkynylcarbonyl alkylcarbonyl arylalkylcarbonyl aminocarbonylaminoalkyl-aryloxyalkyl carbonyl aryloxyalkylcarbonyl aminothiocarbonylamino-substituted aryloxy- alkylcarbonyl alkylcarbonyl arylalkenylcarbonylhaloalkylcarbonyl carboxyalkylcarbonyl hydroxyalkylcarbonylalkoxycarbonylalkyl- haloalkyloxyalkylcarbonyl carbonylcycloalkyloxyalkyl- aminocarbonylalkyl- carbonyl carbonylalkoxyalkylcarbonyl aminothiocarbonyl- cycloalkylalkylcarbonylalkylcarbonyl alkoxycarbonyl aminosulfonealkyl- substituted alkyl-carbonyl carbonyl arylalkynylcarbonyl aryloxyalkoxyalkyl-heterocycloalkylcarbonyl carbonyl heteroarylalkyl alkylcarbonyloxyalkyl-heteroaryloxyalkyl carbonyl heteroarylthiaalkyl- arylcarbonyloxyalkyl-carbonyl carbonyl heterocyclooxyalkyl- aminoalkylcarbonyl carbonylalkylcarbonylamino- hetercyclothiaalkyl- alkylcarbonyl carbonylarylcarbonylaminoalkyl- arylthiaalkylcarbonyl monohaloalkylcarbonylhaloalkyloxyalkyl- carbonyl cycloalkylalkyloxyalkyl- carbonyl

More preferably, R may be selected from among: alkenylcarbonyl,arylalkylcarbonyl, haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, substituted alkyl-carbonyl, aminoalkylcarbonyl,arylalkenylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbony, heteroarylalkylcarbonyl,heteroaryloxyalkylcarbonyl, heterocyclooxyalkylcarbonyl,arylthiaalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkylalkyloxyalky; of which alkenylcarbonyl, arylalkylcarbonyl,haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, substituted alkyl-carbonyl, aminoalkylcarbonyl,arylalkenylcarbonyl, heterocycloalkylcarbony, heteroarylalkylcarbonyl,heteroaryloxyalkylcarbonyl and haloalkyloxyalkylcarbonyl areparticularly preferred, and arylalkylcarbonyl, haloalkylcarbonyl,haloalkyloxyalkylcarbonyl, cycloalkylalkylcarbonyl, aminoalkylcarbonyland haloalkyloxycarbonyl.

Still other N-substituents which are preferred for purposes of potency,efficacy, formulation ability, toxicity and/or cost include:

TABLE 14 aryloxyalkoxyalkyl alkyl substituted alkyl alkenyl aminoalkylarylalkenyl arylcarbonylaminoalkyl aminocarbonylalkylalkoxycarbonylamino- aminosulfonealkyl alkyl arylalkynylaminocarbonylamino- heterocycloalkyl heteroaryloxyalkyl heteroarylalkylheteroarylthiaalkyl heterocyclooxyalkyl cycloalkyloxyalkylheterocyclothiaalkyl cycloalkylalkyloxy- aryloxyalkyl alkylarylthiaalkyl monohaloalkyl haloalkyloxyalkyl

Certain compounds of Formula I are novel compounds of this invention.Novel compounds of Formula I include compounds in which R is among thefollowing:

TABLE 15 aryloxyalkyl substituted- aryloxyalkyl monohaloalkylhaloalkyloxyalkyl carbonyl cycloalkyloxyalkyl cycloalkylalkyloxyalkylalkenylcarbonyl alkynylcarbonyl arylalkylcarbonyl substituted-arylalkylcarbonyl arylalkyloxycarbonyl aryloxyalkylcarbonyl substitutedaryloxyalkylcarbonyl haloalkylcarbonyl hydroxyalkylcarbonylhaloalkyloxyalkyl- carbonyl cycloalkyloxyalkyl- carbonylalkoxyalkylcarbonyl

Of the compounds of Table 15, the substituted alkyls are basic compoundswhich are advantageous in forming stable, water soluble, non-volatilepharmaceutically acceptable salts, preferably with strong acids. Thecarbonyl compounds of Table 15, like those of Table 13, are adapted foruse either as antiviral therapeutic compounds or as intermediates forthe preparation of other N-substituted-glucamine compounds of theinvention and/or useful in the methods thereof. Of the carbonylcompounds of Table 15, arylalkylcarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, haloalkyloxyalkylcarbonyl, andcycloalkyloxyalkylcarbonyl are the more preferred.

Particularly preferred are compounds in which at least one of R andR⁵conforms to R⁷ or R⁸;, and especially compounds wherein R and/or R⁵ isselected from among aryloxyalkyl, monooalkyl, haloalkyloxyalkyl,cycloalkyloxyalkyl, and cycloalkylalkyloxyalkyl. In another useful groupof compounds, R and/or R⁵ is selected from among alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, substituted arylalkylcarbonyl,arylalkyloxycarbonyl, aryloxyalkylcarbonyl, substitutedaryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl,haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, andalkoxyalkylcarbonyl.

Compounds in which R or R⁵ conforms to R⁷ or R⁸ are highly preferred,especially the ethers (where each of any of X¹ through X⁴ are oxygen orsulfur, preferably oxygen), R¹ is alkyl or haloalkyl, and each of any ofR² through R⁴ is independently alkylene or haloalkylene. The di- andtriethers are particularly preferred, as are the R⁷/R⁸ substituents inwhich R¹ or R⁹ is trifluoroalkyl.

Compounds in which A, B, C, and D are hydrido are particularly preferredfor administration in the treatment of hepatitis infections. However,compounds with other combinations of A, B, C and D subsituents andconfigurations (including ring structures as described hereinabove) areuseful as therapeutic agents and as intermediates for the synthesis ofother compounds of Formula I. Where used as therapeutic agents, many ofthese substituted glucamines especially the esters and ethers, functionas prodrugs.

Non-limiting illustrative preparation procedures are presented below inExamples 1 and 2 and Scheme 1 through and including Scheme 3.

Procedures are provided in the discussion and schemes that follow ofexemplary chemical transformations that can be useful for thepreparation of compounds of this invention. R, A, B, C and D are asdefined hereinabove. P is a protecting group and L is a leaving groupboth of which are as defined and in book by Green referenced below.These syntheses, as with all of the reactions discussed herein, can becarried out under a dry inert atmosphere such a nitrogen or argon ifdesired. Selected reactions known to those skilled in the art, can becarried out under a dry atmosphere such as dry air whereas othersynthetic steps, for example, aqueous acid or base ester or amidehydrolyses, can be carried out under ambient air.

In general, the choices of starting material and reaction conditions canvary as is well know to those skilled in the art. Usually, no single setof conditions is limiting because variations can be applied as requiredand selected by one skilled in the art. Conditions will also will beselected as desired to suit a specific purpose such as small scalepreparations or large scale preparations. In either case, the use ofless safe or less environmentally sound materials or reagents willusually be minimized. Examples of such less desirable materials arediazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, somehalogenated solvents, benzene and the like. In addition, many startingmaterials can be obtained from commercial sources from catalogs orthrough other arrangements.

Reaction media can be comprised of a single solvent, mixed solvents ofthe same or different classes or serve as a reagent in a single or mixedsolvent system. The solvents can be protic, non-protic or dipolaraprotic. Non-limiting examples of protic solvents include water,methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanoland the like.

Typical non-protic solvents include acetone, tetrahydrofurane (THF),dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics such asxylene, toluene, or benzene, ethyl acetate, methyl acetate, butylacetate, trichloroethane, methylene chloride, ethylenedichloride (EDC),hexane, heptane, isooctane, cyclohexane and the like.

Dipolar aprotic solvents include compounds such as dimethylformamide(DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane,tetramethylurea, N-methylpyrrolidone and the like.

Non-limiting examples of reagents that can be used as solvents or aspart of a mixed solvent system include organic or inorganic mono- ormulti-protic acids or bases such as hydrochloric acid, phosphoric acid,sulfuric acid, acetic acid, formic acid, citric acid, succinic acid,triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine,piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols oramines for making esters or amides or thiols for making the products ofthis invention 2,4,5,7,9,10 and the like.

Room temperature or less or moderate warming (−10° C. to 60° C.) are thepreferred temperatures of the synthesis and/or transformations of thecompounds of this invention. If desired, the reaction temperature canrange from about −78° C. to the reflux point of the reaction solvent orsolvents. Colder temperatures such as that of liquid nitrogen may bedesired on accasion especially if improved selectivity is required.Higher temperatures may also be used preferably in a pressure containersystem, i.e., a pressure bomb.

Examples of bases that can be used include, for example, metalhydroxides such as sodium, potassium, lithium or magnesium hydroxide,oxides such as those of sodium, potassium, lithium, calcium ormagnesium, metal carbonates such as those of sodium, potassium, lithium,calcium or magnesium, metal bicarbonates such as sodium bicarbonate orpotassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°)organic amines such as alkyl amines, arylalkyl amines, alkylarylalkylamines, heterocyclic amines or heteroaryl amines, ammonium hydroxides orquaternary ammonium hydroxides. As non-limiting examples, such aminescan include triethyl amine, trimethyl amine, diisopropyl amine,methyldiisopropyl amine, diazabicyclononane, tribenzyl amine,dimethylbenzyl amine, morpholine, N-methylmorpholine,N,N′-dimethylpiperazine, N-ethylpiperidine,1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine,quinoline, tetramethylethylenediamine and the like.

Non-limiting examples of ammonium hydroxides, usually made from aminesand water, can include ammonium hydroxide, triethyl ammonium hydroxide,trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide,tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide,morpholinium hydroxide, N-methylmorpholinium hydroxide,N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, andthe like. As non-limiting examples, quaternary ammonium hydroxides caninclude tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide,dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammoniumhydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethylmorpholinium hydroxide,N,N,N′,N′,-tetramethylpiperazenium hydroxide, andN-ethyl-N′-hexylpiperidinium hydroxide and the like. Metal hydrides,amide or alcoholates such as calcium hydride, sodium hydride, potassiumhydride, lithium hydride, sodium methoxide, potassium tert-butoxide,calcium ethoxide, magnesium ethoxide, sodium amide, potassiumdiisopropyl amide and the like can also be suitable reagents.Organometallic deprotonating agents such as alkyl or aryl lithiumreagents such as methyl, phenyl, butyl, iso-butyl, sec-butyl ortert-butyl lithium, sodium or potassium salts of dimethylsulfoxide,Grignard reagents such as methylmagnesium bromide or methymagnesiumchloride, organocadium reagents such as dimethylcadium and the like canalso serve as bases for causing salt formation or catalyzing thereaction. Quaternary ammonium hydroxides or mixed salts are also usefulfor aiding phase transfer couplings or serving as phase transferreagents. Preferred base for use in the alkylation reaction is lithiumdiisopropyl amide as mentioned above.

A further use of bases is for the preparation of pharmaceuticallyacceptable salts discussed herein. These include those listed above withmetal carbonates, bicarbonates, amines, quaternary amines, hydroxidesand various polymeric bases being preferred.

Acids are used in many reactions during various synthesis and for thepreparation of pharmaceutical salts. The Schemes as well as thisdiscussion preparative methods illustrate acid use for the removal ofthe THP protecting group to produce a hydroxamic acid, removal of atert-butoxy carbonyl group, hydroxylamine/ester exchange and the like.Acid hydrolysis of carboxylic acid protecting groups or derivatives iswell known in the art. These methods, as is well known in the art, canuse acid or acidic catalysts. The acid can be mono-, di- or tri-proticorganic or inorganic acids. Examples of acids include hydrochloric acid,phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid,succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid,phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonicacid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methanesulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid,trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid,trinitrobenzoic acid, and the like. They can also be Lewis acids such asaluminum chloride, borontrifluoride, antimony pentafluoride and thelike.

Salts of the compounds or intermediates of this invention are preparedin the normal manner wherein acidic compounds are reacted with basessuch as those discussed above to produce metal or nitrogen containingcation salts. Basic compounds such as amines can be treated with an acidto form an amine salt. If the acid component of the salt is a weakeracid it is preferred that the base component be a stronger base. If thebase component of the salt is with a weaker base it is preferred thatthe acid component be a stronger acid. Thus, the salts preferably have arelatively low pKa, preferably less than about 4.5. Most preferred aresales of relatively strongly basic imino sugars with strong acids.Pharmaceutically acceptable acids and bases for forming salts are wellknown in the art. Salts of the glucamines of this invention andanti-viral and anti-cancer nucleosides/nucleotides are pharmaceuticallyacceptable salts.

Treatment of an amine in with an aldehyde or ketone under reducingconditions will produce a secondarry or tertiary amine of this inventionsuch as 2, 7, 13, 14 or 15. Preferred solvents include, depending on thereducing agent, alcohols or tetrahydrofurane (THF). An inert atmosphereor dry atmosphere is used again depending upon the reactivity of thereducing agent. Hydrogen gas is the usual atmosphere for catalyticreductions. These reducing agents are well known in the art. Reductivealkylation is carried out by adding R—CHO to an amine such as DNJ andtreating with a reducing agent such as sodium cyanoborohydride orcarrying out a catalytic reduction with, for example, a metal catalystand hydrogen gas. Such reducing agents are well known in the art andinclude such reagents as borane, borane:THF, borane:pyridine, lithiumaluminum hydride, aluminum hydride, lithium borohydride, sodiumborohydride potassium triacetylborohydride and the like. Alternatively,reductive alkylation can be carried out under hydrogenation conditionsin the presence of a metal catalyst. Catalysts, hydrogen pressures andtemperatures are discussed and are well known in the art. A desirable“hydride type” reductive alkylation catalyst is borane:pyridine complex.Reductive alkylation or hydrogenation's can be carried out atatmospheric pressure and higher pressures can be used if desired.Catalysts include, for example, Pd, Pd on Carbon, Pt, PtO₂ and the like.Less robust catalysts (deactivated) include such thing as Pd on BaCO₃ orPd with quinoline or/and sulfur can be used in situations whereinselectivity is desired.

Acylation of substrates 1, 6, or 13, as shown in the reaction schemesset out above, can be carried out in standard fashion wherein the amineis treated with a carbonyl compound with a leaving group attached as isdiscussed in textbooks of organic chemistry. The leaving group isdesignated as “L” in the Schemes and may be different in the case of,for example, carboxylic acid derivatives, SN₂ substrates and SN₁substrates and the addition-elimination process with carbonyl typecompounds. Well know acylating groups including those with leavinggroups include halides, anhydrides, mixed anhydrides, ketenes as well asexchangeable groups such as ester groups. Coupling with an activatedester synthesized in situ is also a useful process for preparing amidesand it is discussed below. For example, compound 1, 4, 6, 7, or 13 istreated with an acid chloride in the presence of, preferably, a tertiaryamine base under an inert atmosphere at between about −10° C. and 0° C.The product of this reaction is an amide 3 or 8 of this invention. Apreferred acid activating group (L) is the chloride prepared by, forexample, reaction of an acid with oxalyl chloride, phosphorustrichloride and the like. These carboxylic acids can be derivatized withprotecting group or hydrolyzed to the acid as required.

Compounds 3 , 8 or 15 are reduced to produce 4 or 9, respectively, as aproducts of this invention. The reduction is carried out usingprocedures and reagents as discussed hereinabove and other methods asindicated. Reduction of amides is well known in the art.

Amides such as 3, 8, 13, 14 or 15 can be hydrolyzed if desired. Basehydrolysis or acid hydrolysis methods are well known and the choice ofsystems will depend upon factors determined by the chemist. For example,the presence of base labile substituents might cause a scientist toselect an acid hydrolysis process. Bases that can be used are listedherein. Acids are also discussed above and hydrogen chloride,toluenesulfonic acid and trifluoroacetic acid being preferred. Acidcatalyzed exchange processes are also useful for converting compound 3or 8 into other analogs or into 1 or 6.

Compounds 1, 4, 6, 7, or 13 are also able to be protected as is shown bythe preparation of 5, 10, 14 and 15, respectively. The group P in, forexample, 5, 10, 14 and 15, is a special case of R wherein the group maybe useful for treating disease and also useful for the preparation ofother compounds of this invention. Protecting groups, P, are well knowin organic chemistry along with protection/deprotection processes. Theyare frequently used to control reaction sites, reaction selectivities,help with resolutions such as optical resolutions, aid in purificationprocesses and prevent over reaction in preparation processes. It shouldbe noted that protection of groups other than nitrogen is common in theart with non-limiting examples being hydroxyl groups, thiol groups,carbonyl groups, phosphorus groups, silicon groups and the like and thatP is used to indicate protecting groups in these cases also. It shouldalso be noted that protecting groups and protection/deprotectionreaction sequences are well know in the art of natural product chemistryincluding sugar chemistry and amino acid/peptide chemistry. Editions ofthe books by Thedora Green, e.g., Green, T., Protecting Groups inOrganic Chemistry, Second ed., John Wiley & Sons, New York (1991), areuseful in this regard and are incorporated herein by reference.

As mentioned above, contemplated compounds can include compounds whereina nitrogen of an amine is acylated to provide, for example, amino acidcarbamates. Non-limiting examples of these carbamates are thecarbobenzoxycarbonyl (Z, CBZ, benzyloxycarbonyl), iso-butoxycarbonyl andtert-butoxycarbonyl (BOC, t-BOC) compounds. The materials can be made atvarious stages in the synthesis based on the needs and decisions made bya person skilled in the art using methods well know in the art.

Useful synthetic techniques and reagents for the preparation of thecompounds of this invention include those used in protein, peptide andamino acid synthesis, coupling and transformation chemistry. The use ofthe tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z) as will as theirsynthesis and removal are examples of such protection or synthesisschemes. This includes, for example, active ester or mixed anhydridecouplings wherein preferred bases, if required, are tertiary amines suchas N-methylmorpholine. Reagents for protection of the amine group of theprotected amino acids include carbobenzoxy chloride,iso-butylchloroformate, tert-butoxycarbonyl chloride, di-tert-butyldicarbonate and the like which are reacted with the amine in non-proticor dipolar aprotic solvents such as DMF or THF or mixtures of solvents.

Removal of protecting groups on nitrogen, oxygen, sulfur or other groupssuch as carbamates, silyl groups, THP ethers, enol ethers, ketals,acetals, hemiacetals, hemi-ketals, methoxymethyl ethers, benzyl,p-methoxybenzyl, or other substituted benzyl groups, acyl or aroylgroups or diphenylmethyl (benzhydryl) or triphenylmethyl (trityl) can becarried out at different stages in the synthesis of the compounds ofthis invention as required by methods selected by one skilled in theart. These methods are well known in the art including the amino acid,amino acid coupling, peptide synthesis, peptide mimetic synthesis art.Removal methods can include catalytic hydrogenation, base hydrolysis,carbonyl addition reactions, acid hydrolysis, exchange and the like.Both the preparation and removal of protecting groups, for example,carbamates, trifluoroacetate groups, benzyl groups and/or substitutedarylalkyl groups is discussed in Green, T., Protecting Groups in OrganicChemistry, Second ed., John Wiley & Sons, New York (1991) as discussedabove. A preferred method of removal of a BOC group is HCl gas inmethylene chloride which, following normal workup, provides directly anHCl salt of an amine of this invention, i.e., an ammoniun salt. Apreferred method of removing a Z group is cataleptic reduction.

Alkylation of amines such as 1, 4, 6, 7, 9, 13 or 14 is accomplished bymethods well known in the art and discussed in textbooks of organicchemistry. The process is via SN₂ or SN₁ displacement of a leavinggroup, L, on a substrate by the amine. The amine is treated in a solventsuch as those discussed above like DMSO, DMF, methanol, ethanol, THF,acetone and the like. Leaving groups can include halides, sulfonic acidesters such as tosylates, mesylates, triflates, trifluoroacetates andthe like. The reaction can be carried out under an inert atmosphere ordry, non-oxidative conditions. An inert atmosphere is preferred.

Scheme 2 illustrates the application of the methods discussed for thepreparation of compounds wherein A, B, C and D are hydrogen. It is to benoted that the syntheses may proceed in the presence of the hydroxylgroups thus the chemist has options in selecting the compound to besynthesized as well as the synthetic route to the compound.

Scheme 3 illustrates the preparation of open chain sugars containingamines 13, 14, or 15, amides 14 and 15 or protected amines 15 and 14 andimine 12. The reductive alkylation, hydrolysis, reduction, protection,deprotection, and alkylation processes have been discussed above. Theinterconversion of, for example, hydroxyl groups can be carried out byalkyation or acylation by processes discussed above and well know in theart. Treatment with an aldehyde, aldimine, ketone or ketimine under, forexample, acid contitions in a non-protic or dipolar aprotic solvent,produces heterocycles such as those presented above.

Scheme 3 illustrates the used of glucose, sorbose other open chainsugars and their derivatives in the preparation of 2. For example,glucose is reacted with a primary amine R—NH₂ or a derivative of the Rgroup in R—NH₂ to produce a putative imine derivative 12. R is asdefined above (including hydrogen with the use of ammonia) andpreferably not connected via a carbonyl carbon. Reaction can be with orwithout heating and with or without a catalyls such as an acid catalyst.Removal of water during imine formation from the putative open chainaldehyde intermediate is possible if desired. Reduction using methodsdiscussed above including metal catalyzed hydrogenations produce theopen chain compound 13.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers such as enantiomers, racemates and diastereoisomers as well asin the form of racemic or nonracemic mixtures thereof. The opticalisomers can be obtained by resolution of the racemic mixtures accordingto conventional processes well known in the art, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base.

Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, natural aminoacids andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers.

Still another available method involves synthesis of covalentdiastereoisomeric molecules, e.g., esters, amides, acetals, ketals, andthe like, by reacting compounds of Formula I with an optically activeacid in an activated form, a optically active diol or an opticallyactive isocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomericaly purecompound. In some cases hydrolysis to the parent optically active drugis not necessary prior to dosing the patient since the compound canbehave as a prodrug. The optically active compounds of Formula I canlikewise be obtained by utilizing optically active starting materials.

In addition to the optical isomers or potentially optical isomersdiscussed above, other types of isomers are specifically intended to beincluded in this discussion and in this invention. Examples include cisisomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers,tautomers, rotamers and the like. Aryl, heterocyclo or heteroaryltautomers, heteroatom isomers, heterocyclo or heteroaryl heteroatomisomers and ortho, meta or para substitution isomers are also includedas isomers as are multicyclic isomers such as those of thephenanthrene/anthracene type and the multicyclic saturated or partiallyunsaturated type. The latter type of isomer is exemplified in general bybicyclo[2,2,2]octane and bicyclo[3,2,1]octane. Solvates or solventaddition compounds such as hydrates or alcoholates are also specificallyincluded both as chemicals of this invention and in, for example,formulations or pharmaceutical compositions for drug delivery.

Where a substituent is designated as, or can be, a hydrogen, the exactchemical nature of a substituent which is other than hydrogen at thatposition, e.g., a hydrocarbyl radical or a halogen, hydroxy, amino andthe like functional group, is not critical so long as it does notadversely affect the overall activity and/or synthesis procedure. Forexample, two hydroxyl groups, two amino groups, two thiol groups or amixture of two hydrogen-heteroatom groups on the same carbon are knownnot to be stable without protection or as a derivative.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions can not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Other compounds of this invention that are acids can also form salts.Examples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases orbasic quaternary ammonium salts.

In some cases, the salts can also be used as an aid in the isolation,purification or resolution of the compounds of this invention.

Prodrugs are drugs that can be chemically converted in vivo or in vitroby biological systems into an active drug or drugs, i.e., it is apharmaceutically acceptable bioprecursor of a desired pharmaceutical orpharmaceuticals. The prodrug can be a compound having a structuralformula different from the active compound but which upon administrationto a mammal or in vitro system is converted into a compound of thisinvention. Such prodrugs are also compounds of this invention useful forthe treatment of human, agricultural and general veterinary diseases.

In treating hepatitis B virus or hepatits C virus infections, one canuse the present substitututed-glucamine compounds alone or incombination in the form of salts derived from inorganic or organicacids. These salts include but are not limited to the following:acetate, adipate, alginate,

citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate.

The basic nitrogen-containing groups can be quaternized with agents suchas lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides, and iodides; dialkyl sulfates such as dimethyl,diethyl, dibuytl, and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkylhalides such as benzyl and phenethyl bromides, and others. Water- oroil-soluble or dispersible products are thereby obtained as desired. Thesalts are formed by combining the basic compounds with the desired acid.

Nucleosides and Nucleotides

Nucleosides and nucleotides useful in the present invention are purine(II) base compounds or pyrimidine (III) base compounds, or analogs suchas compounds IV, V or VI.

Position numbering for purines and pyrmidines is as shown in structuresII and III. R¹ can be selected from hydroxyalkyl, hydroxyalkenyl,carboxyalkyl, carboxyalkenyl, thiolalkyl, alkylthioalkyl, alkoxyalkyl,alkoxyalkenyl, heterocycle, heterocyclo-alkyl, hydroxyalkylalkoxyalkyl,alkoxyalkylalkoxyalkyl, and cycloalkylalkyl. The purine compounds can befurther substituted at positions 1, 2, 3, 6, 7, or 8 of the purineheterocycle, and the pyrimidine compounds can be substituted atpositions 2, 3, 4, 5, or 6 of the pyrimidine heterocycle. Suchsubstituents can be selected from hydroxy, alkoxy, halo, thiol, amino,carboxyl, mono-substituted amino, di-substituted amino, and alkyl.

The following definitions are applicable only to the structures ofFormulas II, III, IV, V and VI of this invention. When used incombination with another radical when referring to the purines andpyrimidines useful in the present invention, the term “alkyl” means astraight or branched chain hydrocarbon radical containing from 1 to 8carbon atoms, preferably 1 to 4 carbon atoms. When used in combinationwith another radical, the term “alkenyl” means a straight or branchedchain hydrocarbon radical having 1 or more double bonds, containing from2 to 8 carbon atoms, preferably 1 to 4 carbon atoms. When used alonewhen referring to purines and pyrimidines useful in the presentinvention, the term “alkyl” means a straight or branched chain alkylradical containing from six to 14 carbon atoms, preferably seven to 12carbon atoms, and most preferably eight to 11 carbon atoms. The term“aryl” alone or in combination with another radical means a phenyl,naphthyl, or indenyl ring, optionally substituted with one or moresubstituents selected from alkyl, alkoxy, halogen, hydroxy, or nitro.“Alkanoyl” means branched or straight chain alkanecarbonyl having achain length of C, to C₂₀, preferably C₂ to C₁₄, more preferably C₄ toC₁₀; “aroyl” means arylcarbonyl; and “trifluoroalkanoyl” means alkylcontaining three fluoro substituents. “Halogen” means fluorine,chlorine, bromine, or iodine. “Thiol” means sulfur substituted withhydrogen (—SH). “Amino” means nitrogen with two hydrogen atoms;“monosubstituted amino” and “disubstituted amino” mean amino groupsfurther independently substituted with one or more alkyl or arylalkylgroups. “Hydroxyalkyl” means an alkyl group substituted with one or morehydroxyl groups; “hydroxy-alkenyl” means an alkenyl group substitutedwith one or more hydroxyl groups; “thioalkyl”, means an alkylsubstituted with one or more thiol (SH) groups; “alkoxyalkyl” means analkyl substituted with one or more alkyl ether groups; “alkoxyalkenyl”means an alkenyl group substituted with one or more alkyl ether groups;“hydroxyalkylalkoxyalkyl” means an alkoxyalkyl group substituted with ahydroxyalkyl group; “alkoxyalkyl-alkoxyalkyl” means an alkoxyalkyl groupsubstituted with an alkoxyalkyl group; “cycloalkylalkyl” means an alkylgroup substituted with a cycloalkyl group. The term “heterocycle,” aloneor in combination, means a saturated or partially unsaturated 5 or6-membered ring containing one or more oxygen, nitrogen, and/or sulfurheteroatoms. Said heterocycle can further be substituted with one tofour substituents, which can be independently, hydroxy, hydroxyalkyl,thiol, alkoxy, azido, nitro, a halogen atom, amino, mono-substitutedamino, or disubstituted amino. Heterocycloalkyl means an alkyl groupwherein one or more hydrogen atoms are replaced by a substituted orunsubstituted heterocyclic ring.

Also included are the tautomers of the substituents on the compounds ofthe invention. Non-limiting examples of tautomers are ketone/enoltautomers, imino/amino tautomers, N-substituted imino/N-substitutedamino tautomers, thiol/thiacarbonyl tautomers, and ring-chain tautomerssuch as the five and six membered ring oxygen, nitrogen, sulfur, oroxygen- and sulfur-containing heterocycles also containing substituentsalpha to the heteroatoms. Also specifically included in the presentinvention are enantiomers and diastereomers, as well as racemates andisomeric mixtures of the compounds discussed herein.

Representative nucleoside and nucleotide compounds useful in the presentinvention include, but are not limited to:

(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;

(−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC);

(−)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine(FTC);

(−)2′,3′, dideoxy-3′-thiacytidine [(−)-SddC];

1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC);

1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosinetriphosphate (FIACTP);

1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU);

1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide;

2′,3′-dideoxy-3′-fluoro-5-methyl-dexocytidine (FddMeCyt);

2′,3′-dideoxy-3′-chloro-5-methyl-dexocytidine (ClddMeCyt);

2′,3′-dideoxy-3′-amino-5-methyl-dexocytidine (AddMeCyt);

2′,3′-dideoxy-3′-fluoro-5-methyl-cytidine (FddMeCyt);

2′,3′-dideoxy-3′-chloro-5-methyl-cytidine (ClddMeCyt);

2′,3′-dideoxy-3′-amino-5-methyl-cytidine (AddMeCyt);

2′,3′-dideoxy-3′-fluorothymidine (FddThd);

2′,3′-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);

2′,3′-dideoxy-beta-L-5-thiacytidine;

2′,3′-dideoxy-beta-L-5-cytidine (beta-L-ddC);

9-(1,3-dihydroxy-2-propoxymethyl)guanine;

2′-deoxy-3′-thia-5-fluorocytosine;

3′-amino-5-methyl-dexocytidine (AddMeCyt);

2-amino-1,9-[(2-hydroxymethyl-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one(gancyclovir);

2-[2-(2-amino-9H-purin-9y)ethyl]-1,3-propandil diacetate (famciclovir);

2-amino-1,9-dihydro-9-[(2-hydroxy-ethoxy)methyl]6H-pur in-6-one(acyclovir);

9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine (penciclovir);

9-(4-hydroxy-3-hydroxymethyl-but-1-yl)-6-deoxy-guanine, diacetate(famciclovir);

3′-azido-3′-deoxythymidine (AZT);

3′-chloro-5-methyl-dexocytidine (ClddMeCyt);

9-(2-phosphonyl-methoxyethyl)-2′,6′-diaminopurine-2′,3′-dideoxyriboside;

9-(2-phosphonylmethoxyethyl)adenine (PMEA);

acyclovir triphosphate (ACVTP);

D-carbocyclic-2′-deoxyguanosine (CdG);

dideoxy-cytidine;

dideoxy-cytosine (ddC);

dideoxy-guanine (ddG);

dideoxy-inosine (ddI);

E-5-(2-bromovinyl)-2′-deoxyuridine triphosphate;

fluoro-arabinofuranosyl-iodouracil;

1-(2′-deoxy-2′-fluoro-1-beta-D-arabinofuranosyl)-5-iodo-uracil (FIAU);

stavudine;

9-beta-D-arabinofuranosyl-9H-purine-6-amine monohydrate (Ara-A);

9-beta-D-arabinofuranosyl-9H-purine-6-amine-5′-monophosphate monohydrate(Ara-AMP);

2-deoxy-3′-thia-5-fluorocytidine;

2′,3′-dideoxy-guanine; and

2′,3′-dideoxy-guanosine.

A preferred compound is (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate(3TC).

Synthetic methods for the preparation of nucleosides and nucleotidesuseful in the present invention are likewise well known in the art asdisclosed in Acta Biochim. Pol., 43, 25-36 (1996); Swed. NucleosidesNucleotides 15, 361-378 (1996), Synthesis 12, 1465-1479 (1995),Carbohyd. Chem. 27, 242-276 (1995), Chem. Nucleosides Nucleotides 3,421-535 (1994), Ann. Reports in Med. Chem., Academic Press; and Exp.Opin. Invest. Drugs 4, 95-115 (1995).

The chemical reactions described in the references cited above aregenerally disclosed in terms of their broadest application to thepreparation of the compounds of this invention. Occasionally, thereactions may not be applicable as described to each compound includedwithin the scope of compounds disclosed herein. The compounds for whichthis occurs will be readily recognized by those skilled in the art. Inall such cases, either the reactions can be successfully performed byconventional modifications known to those skilled in the art, e.g., byappropriate protection of interfering groups, by changing to alternativeconventional reagents, by routine modification of reaction conditions,and the like, or other reactions disclosed herein or otherwiseconventional will be applicable to the preparation of the correspondingcompounds of this invention. In all preparative methods, all startingmaterials are known or readily preparable from known starting materials.

While nucleoside analogs are generally employed as antiviral agents asis, nucleotides (nucleoside phosphates) must sometimes have to beconverted to nucleosides in order to facilitate their transport acrosscell membranes. An example of a chemically modified nucleotide capableof entering cells is S-1-3-hydroxy-2-phosphonylmethoxypropyl cytosine(HPMPC, Gilead Sciences).

Nucleoside and nucleotide compounds of this invention that are acids canform salts. Examples include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium, or magnesium, or withorganic bases or basic quaternary ammonium salts.

Immunomodulators and Immunostimulants

A large number of immunomodulators and immuno-stimulants that can beused in the methods of the present invention are currently available. Alist of these compounds is provided in Table 1, below.

TABLE 1 AA-2G adamantylamide dipeptide adenosine deaminase, Enzonadjuvant, Alliance adjuvants, Ribi adjuvants, Vaxcel Adjuvaxagelasphin-11 AIDS therapy, Chiron algal glucan, SRI algammulin, AnutechAnginlyc anticellular factors, Yeda Anticort antigastrin-17 immunogen,Ap antigen delivery system, Vac antigen formulation, IDBC antiGnRHimmunogen, Aphtoh Antiherpin Arbidol azarole Bay-q-8939 Bay-r-1005BCH-1393 Betafectin Biostim BL-001 BL-009 Broncostat CantastimCDRI-84-246 cefodizime chemokine inhibitors, ICOS CMV peptides, City ofHope CN-5888 cytokine-releasing agent, St DHEAS, Paradigm DISC TA-HSVJ07B I01A I01Z ditiocarb sodium ECA-10-142 ELS-1 endotoxin, NovartisFCE-20696 FCE-24089 FCE-24578 FLT-3 ligand, Immunex FR-900483 FR-900494FR-901235 FTS-Zn G-proteins, Cadus gludapcin glutaurineglycophosphopeptical GM-2 GM-53 GMDP growth factor vaccine, EntreMH-BIG, NABI H-CIG, NABI HAB-439 Helicobacter pylori vaccine,herpes-specific immune factor HIV therapy, United Biomed HyperGAM + CFImmuMax Immun BCG immune therapy, Connective immunomodulator, Evansimmunomodulators, Novacell imreg-1 imreg-2 Indomune inosine pranobexinterferon, Dong-A (alpha2) interferon, Genentech (gamma) interferon,Novartis (alpha) interleukin-12, Genetics Ins interleukin-15, Immunexinterleukin-16, Research Cor ISCAR-1 J005x L-644257 licomarasminic acidLipoTher LK-409 LK-410 LP-2307 LT(R1926) LW-50020 MAF, Shionogi MDPderivatives, Merck met-enkephalin, TNI methylfurylbutyrolactones MIMPmirimostim mixed bacterial vaccine, Tem MM-1 moniliastat MPLA, RibiMS-705 murabutide murabutide, Vacsyn muramyl dipeptide derivativemuramyl peptide derivatives myelopid N-563 NACCS-6 NH-765 NISV, ProteusNPT-16416 NT-002 PA-485 PEFA-814 peptides, Scios peptidoglycan, PlivaPerthon, Advanced Plant PGM derivative, Pliva Pharmaprojects No. 1099Pharmaprojects No. 1426 Pharmaprojects No. 1549 Pharmaprojects No. 1585Pharmaprojects No. 1607 Pharmaprojects No. 1710 Pharmaprojects No. 1779Pharmaprojects No. 2002 Pharmaprojects No. 2060 Pharmaprojects No. 2795Pharmaprojects No. 3088 Pharmaprojects No. 3111 Pharmaprojects No. 3345Pharmaprojects No. 3467 Pharmaprojects No. 3668 Pharmaprojects No. 3998Pharmaprojects No. 3999 Pharmaprojects No. 4089 Pharmaprojects No. 4188Pharmaprojects No. 4451 Pharmaprojects No. 4500 Pharmaprojects No. 4689Pharmaprojects No. 4833 Pharmaprojects No. 494 Pharmaprojects No. 5217Pharmaprojects No. 530 pidotimod pimelautide pinafide PMD-589podophyllotoxin, Conpharm POL-509 poly-ICLC poly-ICLC, Yamasa ShoyuPolyA-PolyU Polysaccharide A protein A, Berlox Bioscience PS34WOpseudomonas MAbs, Teijin Psomaglobin PTL-78419 Pyrexol pyriferoneRetrogen Retropep RG-003 Rhinostat rifamaxil RM-06 Rollin romurtideRU-40555 RU-41821 rubella antibodies, ResCo S-27609 SB-73 SDZ-280-636SDZ-MRL-953 SK&F-107647 SL04 SL05 SM-4333 Solutein SRI-62-834 SRL-172ST-570 ST-789 staphage lysate Stimulon suppressin T-150R1 T-LCEFtabilautide temurtide Theradigm-HBV Theradigm-HPV Theradigm-HSV THF,Pharm & Upjohn THF, Yeda thymalfasin thymic hormone fractionsthymocartin thymolymphotropin thymopentin thymopentin analoguesthymopentin, Peptech thymosin fraction 5, Alpha thymostimulinthymotrinan TMD-232 TO-115 transfer factor, Viragen tuftsin, Selavoubenimex Ulsastat ANGG− CD-4+ Collag+ COLSF+ COM+ DA-A+ GAST− GF-TH+GP-120− IF+ IF-A+ IF-A-2+ IF-B+ IF-G+ IF-G-1B+ IL-2+ IL-12+ IL-15+ IM+LHRH− LIPCOR+ LYM-B+ LYM-NK+ LYM-T+ OPI+ PEP+ PHG-MA+ RNA-SYN− SY-CW−TH-A-1+ TH-5+ TNF+ UN

The substituted glucamine compounds useful in the present invention canbe administered to humans in an amount in the range of from about 0.1mg/kg/day to about 100 mg/kg/day, more preferably from about 1 mg/kg/dayto about 75 mg/kg/day, and most preferably from about 5 mg/kg/day toabout 50 mg/kg/day.

The nucleoside or nucleotide antiviral compound, or mixtures thereof,can be administered to humans in an amount in the range of from about0.1 mg/person/day to about 500 mg/person/day, preferably from about 10mg/person/day to about 300 mg/person/day, more preferably from about 25mg/person/day to about 200 mg/person/day, even more preferably fromabout 50 mg/person/day to about 150 mg/person/day, and most preferablyin the range of from about 1 mg/person/day to about 50 mg/person/day.

Immunomodulators and immunostimulants useful in the present inventioncan be administered in amounts lower than those conventional in the art.For example, thymosin alpha 1 and thymosin fraction 5 are typicallyadministered to humans for the treatment of HepB infections in an amountof about 900 g/m², two times per week (Hepatology (1988) 8:1270;Hepatology (1989) 10:575; Hepatology (1991) 14:409; Gastroenterology(1995) 108:A1127). In the methods and compositions of the presentinvention, this dose can be in the range of from about 10 g/m², twotimes per week to about 750 g/m², two times per week, more preferablyfrom about 100 g/m², two times per week to about 600 g/m², two times perweek, most preferably from about 200 g/m², two times per week to about400 g/m², two times per week. Interferon alfa is typically administeredto humans for the treatment of HepC infections in an amount of fromabout 1×10⁶ units/person, three times per week to about 10×10⁶units/person, three times per week (Simon et al., (1997) Hepatology25:445-448). In the methods and compositions of the present invention,this dose can be in the range of from about 0.1×10⁶ units/person, threetimes per week to about 7.5×10⁶ units/person, three times per week, morepreferably from about 0.5×10⁶ units/person, three times per week toabout 5×10⁶ units/person, three times per week, most preferably fromabout 1×10⁶ units/person, three times per week to about 3×10⁶units/person, three times per week.

Due to the enhanced hepatitis virus antiviral effectiveness of theseimmunomodulators and immunostimulants in the presence of theN-substituted-glucamine compounds useful in the present invention,reduced amounts of other immunomodulators/immunostimulants can beemployed in the methods and compositions disclosed herein. Such reducedamounts can be determined by routine monitoring of hepatitis virus ininfected patients undergoing therapy. This can be carried out by, forexample, monitoring hepatitis viral DNA in patients' serum by slot-blot,dot-blot, or PCR techniques, or by measurement of hepatitis surface orother antigens, such as the e antigen, in serum. Methods therefor arediscussed in Hoofnagle et al., (1997) New Engl. Jour. Med.336(5):347-356, and F. B. Hollinger in Fields Virology, Third Ed., Vol.2 (1996), Bernard N. Fields et al., Eds., Chapter 86, “Hepatitis BVirus,” pp. 2738-2807, Lippincott-Raven, Philadelphia, Pa., and thereferences cited therein.

Patients can be similarly monitored during combination therapy employingN-substituted-glucamine compounds and nucleoside and/or nucleotideantiviral agents to determine the lowest effective doses of each.

The doses described above can be administered to a patient in a singledose or in proportionate multiple subdoses. In the latter case, dosageunit compositions can contain such amounts of submultiples thereof tomake up the daily dose. Multiple doses per day can also increase thetotal daily dose should this be desired by the person prescribing thedrug.

Pharmaceutical Compositions

The compounds of the present invention can be formulated aspharmaceutical compositions. Such compositions can be administeredorally, parenterally, by inhalation spray, rectally, intradermally,transdermally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches oriontophoresis devices. The term parenteral as used herein includessubcutaneous, intravenous, intramuscular, or intrasternal injection, orinfusion techniques. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa. (1975), and Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are usefulin the preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, and polyethylene glycols canbe used. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the compounds discussedherein can be prepared by mixing the active agent with a suitablenon-irritating excipient such as cocoa butter, synthetic mono-, di-, ortriglycerides, fatty acids, or polyethylene glycols which are solid atordinary temperatures but liquid at the rectal temperature, and whichwill therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the compounds can be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets can contain a controlled-release formulation as canbe provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formscan also comprise buffering agents such as sodium citrate, or magnesiumor calcium carbonate or bicarbonate. Tablets and pills can additionallybe prepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The compounds can be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form will vary depending upon thepatient and the particular mode of administration.

Certain of the pharmaceutical compounds of this invention which areadministered in accordance with the methods of the invention can serveas prodrugs to other compounds of this invention. Prodrugs are drugsthat can be chemically converted in vivo or in vitro by biologicalsystems into an active derivative or derivatives. Prodrugs areadministered in essentially the same fashion as the other pharmaceuticalcompounds of the invention. Non-limiting examples are the esters of theN-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of thisinvention.

Compounds of the combinations of this invention, for exampleN-(n-nonenyl)-glucamine and various nucleosides or nucleotides, may beacids or bases. As such, they may be used to form salts with oneanother. Nucleosides are purine or pyrimidine compounds lacking aphosphate ester. Compounds of Formulas II, III, IV, V, or VI hereinwithout a phosphate ester but containing a carboxylic acid moiety couldform a salt with an N-substituted-glucamine compound of the presentinvention. Nucleotides are purine or pyrimidine compounds that aremono-, di-, or triphosphate esters. These phosphate esters contain free-OH groups that are acidic, and that can form salts with inorganic basesor organic bases. Salt formation with organic bases depends on the pKaof the acid and base. CertainN-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds disclosedherein are basic and form pharmaceutically acceptable ammonium orquaternary ammonium salts. In the present case, useful salts can beformed not only with pharmaceutically acceptable acids, but also withbiologically active acids such as the nucelosides and nucleotidesdisclosed herein. These salts can be prepared in the conventional mannerfor preparing salts, as is well known in the art. For example, one cantreat the free base of an N-substituted-glucamine compound with anucleotide analog of Formula II, III, IV, V, or VI to form a salt. Thiscan be performed as a separate chemical reaction, or as part of theformulation process. The limiting reagent in the salt forming reactionis either the acid or base, as selected by the artisan to obtain asuitable biological result. The formulation can contain mixtures ofdifferent salts, acids, or free bases as desired. For example, thephosphoric acid form of (−)-2′-deoxy-3′-thiocytidine-5′-triphosphatewill form a salt with the base form of N-(n-nonenyl)-glucamine orN-(n-nonenyl)-glucamine tetrabutyrate. This type of salt can then beprovided to the patient in a pharmaceutically acceptable formulation, asa pure single salt, or as part of a mixture. These acids and bases canbe independently formulated and maintained in separate compartments inthe same formulation if desired.

In some cases, the salts can also be used as an aid in the isolation,purification, or resolution of the compounds of this invention.

Treatment Regimen

The regimen for treating a patient suffering from a hepatitis virusinfection with the compounds and/or compositions of the presentinvention is selected in accordance with a variety of factors, includingthe age, weight, sex, diet, and medical condition of the patient, theseverity of the infection, the route of administration, pharmacologicalconsiderations such as the activity, efficacy, pharmacokinetic, andtoxicology profiles of the particular compounds employed, and whether adrug delivery system is utilized.

Administration of the drug combinations disclosed herein shouldgenerally be continued over a period of several weeks to several monthsor years until virus titers reach acceptable levels, indicating thatinfection has been controlled or eradicated. As noted above, patientsundergoing treatment with the drug combinations disclosed herein can beroutinely monitored by measuring hepatitis viral DNA in patients' serumby slot-blot, dot-blot, or PCR techniques, or by measurement ofhepatitis antigens, such as hepatitis B surface antigen (HBsAg) andhepatitis B e antigen (HBeAg), in serum to determine the effectivenessof therapy. In chronic hepatitis B, for example, remissions arecharacterized by the disappearance of hepatitis B viral DNA, i.e.,reduction to undetectable levels as measured by hybridization testscapable of detecting levels 10⁵ genomes per ml of serum, and HBeAg fromserum despite the continued presence of HBsAg. These serologic eventsare followed by improvement in the biochemical and histologic featuresof the disease. The end point of successful treatment in most trials ofantiviral therapy is the disappearance of HBeAg and viral DNA fromserum. In patients in whom the e antigen disappears, remission isusually sustained, and results in an inactive HBsAg carrier state. Manypatients eventually become HBsAg-negative (see Hoofnagle et al., (1997)New Engl. Jour. Med. 336(5):347-356 for a review).

Continuous analysis of the data obtained by these methods permitsmodification of the treatment regimen during therapy so that optimalamounts of each component in the combination are administered, and sothat the duration of treatment can be determined as well. Thus, thetreatment regimen/dosing schedule can be rationally modified over thecourse of therapy so that the lowest amounts of each of the antiviralcompounds used in combination which together exhibit satisfactoryanti-hepatitis virus effectiveness are administered, and so thatadministration of such antiviral compounds in combination is continuedonly so long as is necessary to successfully treat the infection.

The following non-limiting examples serve to illustrate various aspectsof the present invention.

EXAMPLE 1 Preparation of 1,5-(butylimino)-1,5-dideoxy-D-glucitol

A solution of 1,5-dideoxy-1,5-imino-D-glucitol (5.14 g, 0.0315 mole),butyraldehyde (3.35 ml, 0.0380 mole) and Pd black (1 g) in 200 mlmethanol was hydrogenated (60 psi/29C/21 hrs.). After filtering theresulting mixture, the filtrate was concentrated in vacuo to an oil. Thetitle compound was crystallized from acetone, and recrystallized frommethanol/acetone, m.p. ca. 132C. The structure assignment was supportedby NMR, infrared spectra and elemental analysis.

Analysis calcd. for C₁₀H₂₁NO₄: C, 54.78; H, 9.65; N, 6.39. Found: C,54.46; H, 9.33; N, 6.46.

EXAMPLE 2 Preparation of 1,5-(butylimino)-1,5-dideoxy-D-glucitol,tetraacetate

Acetic anhydride (1.08 g, 0.0106 mole) was added to the title compoundof Example 1 (0.50 g, 0.0023 mole) in 5 ml pyridine and stirred for 17days at room temperature. The product was evaporated under nitrogen gas.The resulting title compound was purified by silica gel chromatography.Structure assignment was supported by NMR, infrared spectra andelemental analysis.

Analysis calcd. for C₁₈H₂₉NO₈: C, 55.80; H, 7.54; N, 3.62. Found: C,55.42; H, 7.50; N, 3.72.

EXAMPLE 3 Anti-Hepatitis B Virus Activity of VariousN-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compounds In Vitro

The anti-hepatitis B virus activity and effect on cell viability of anumber of different N-substituted-1,5-dideoxy-1,5-imino-D-glucitolcompounds were assessed using an in vitro assay employing chronicallyhepatitis B virus secreting HepG2.2.15 cells. The method employed wasessentially that described in Block et al. (1994) Proc. Natl. Acad. Sci.USA 91:2235-2239. The results are shown in Tables 2 and 3.

TABLE 2 Effect of N-Substituted-1,5-Dideoxy-1,5-Imino-D-GlucitolCompounds on Hepatitis B Virus Secretion and Viability of HepG2.2.15Cells Compound and Relative amount [Concentration]¹ % Viable of HBVsecreted As A % +/−1 S.D.^(2.5) of Control³ Control 90 +/− 7 (n = 4) 100NBDNJ [200] 94 +/− 6 (n = 10) 37.0 +/− 13 (n = 15) NBDNJ [1000] 88 +/− 8(n = 10) 3.2 +/− 5 (n = 15) 1 [200] 90 +/− 2 (n = 4) 85.0 +/− 5 (n = 8)1 [1000] 87 +/− 3 (n = 4) 35.0 +/− 6 (n = 8) 2 [200] 90 +/− 6 (n = 4)107.0 +/− 12 (n = 3) 2 [1000] 89 +/− 4 (n = 4) 38.0 +/− 15 (n = 3) 3[200] n.d.⁴ 45.0 +/− 30 (n = 3) 3 [1000] n.d.⁴ 5.0 +/− 20 (n = 3) 4[200] 93 +/− 1 (n = 4) 60.0 (n = 2) 4 [1000] 91 +/− 3 (n = 4) 34.0 (n =2) 5 [200] 88 +/− 6 (n = 4) 0.0 +/− 0 (n = 3) 5 [1000] 5 +/− 5 (n = 4)0.0 +/− 0 (n = 3) 6 [200] n.d.  58.0 +/− 20 (n = 3) 6 [1000] n.d.  20.0+/− 15 (n = 3) ¹Chronically HBV secreting 2.2.15 cells (approximately500,000 per well) were incubated in the presence of indicated compoundfor three days. ²After 3 days of culture in the absence or presence ofcompound, cells were removed by trypsin treatment, incubated with trypanblue, and visually examined for dye exclusion by microscopy. Values arethe percentage, relative to the total number of cells examined, of cellsexcluding trypan blue (trypan blue exclusion was considered equivalentto viability). ³After 3 days of incubation in the absence or presence ofcompound, secreted virions were immunoprecipitated from the culturemedium with monoclonal antibody specific for preS1 antigen (Meisel etal. (1995) Intervirology 37:330-339; Lu et al. (1995) Virology213:660-665). Viral DNA present in the immunoprecipitates was detectedby densitrometric quantification of the DNA fragment of the correct sizeresulting from a polymerase chain reaction. The amount of # DNAamplified from control (cells receiving no compound) is assumed to be100%. NBDNJ: N-(n-butyl-)-1,5-dideoxy-1,5-imino-D-glucitol; N-butyl DNJ.⁴Although trypan blue viability staining was not performed, cellsappeared unremarkable (healthy) by gross microscopic examination. ⁵S.D.:standard deviation. Compounds: 1:N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol 2:N-(n-butyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate 3:N-(2-ethylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol 4:N-(4,4,4-triflourobutyl)-1,5-dideoxy-1,5-imino-D-glucitol 5:N-(8,8,8-triflourooctyl)-1,5-dideoxy-1,5-imino-D-glucitol 6:N-(6,6,6-triflourohexyl)-1,5-dideoxy-1,5-imino-D-glucitol

TABLE 3 Effect of N-Substituted-1,5-Dideoxy-1,5-Imino-D-GlucitolCompounds on Hepatitis B Virus Secretion and Viability HepG2.2.15 CellsCompound [] for 90% HBV secretion [] for a 50% inhibition¹ reduction inMMT² 1  0.5-1.0* 100-200 2 >200*s* ND 3  200* >200 4  200* >200 5 200* >200 6  >200** >200 7  >200** >200 8  >200** >200 9  >200** >20010 −200   500 ¹in microgs per ml. and based upon duplicate PCR results.²in microgs per ml.; MTT: ³Not determined. *lowest concentration tested.**there was no inhibition seen at the highest concentration used (200microgs/ml). Compounds: 1: N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol2: N-(n-butyl)-1,5-dideoxy-1,5-imino-D-glucitol, diacetate 3:1,5-dideoxy-1,5-imino-D-glucitol, tetracetate 4:N,O-(1,6-carbonyl)-1,5-dideoxy-1,5-imino-D-glucitol 5:N-(n-butyl)-2,3-dimethoxy-1,5-dideoxy-1,5-imino-D-glucitol 6:N-(n-hexyl)-4,6-benzylidine-1,5-dideoxy-1,5-imino-D-glucitol 7:N-(n-butyl)-3-methoxy-1,5-dideoxy-1,5-imino-D-glucitol 8:N-(4,4,4-triflourobutyl)-2,3-dimethoxy-1,5-dideoxy-1,5-imino-D-glucitol,tetracetate 9:N,O-(1,6-methylenecarbonyl)-1,5-dideoxy-1,5-imino-D-glucitol 10:N-(8,8,8-triflourooctyl)-1,5-dideoxy-1,5-imino-D-glucitol MMT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. TheMTT-based colorimetric assay is a measurement of cell viability (Heo etal. (1990) Cancer Research 50:3681-3690)

EXAMPLE 4 Anti-Hepatitis B Virus Activity of(−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC) Alone and inCombination with N-nonyl-DNJ

The anti-hepatitis B virus effect of(−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC) alone and incombination with N-nonyl-DNJ was determined according to Korba ((1996)Antiviral Research 29(1):49-51), using the “combostat” strategy (ComstatProgram, Combostat Corp., Duluth, Minn.). The combostat method involvesserially diluting the IC-90 of each compound. The IC-90 of N-nonyl-DNJhas been determined to be between 4 and 10 g/ml (T. Block and G. Jacob,unpublished observation). The accepted IC-90 for 3TC in HepG 2.2.15(2.2.15) cells is 300 nM to 500 nM (Doong et al. (1991) Proc. Natl.Acad. Sci. USA 88:8495-8499).

2.2.15 cells, described in Sells et al. (1987) Proc. Natl. Acad. Sci.USA 84:1005-1009, were maintained in RPMI 1640 medium (Gibco BRL,#31800-022) supplemented with 10% fetal bovine serum, 200 g/ml G418(Gibco BRL 066-1811). Cells were seeded into 25 cm² flasks at 80%confluency. Five days later, flasks in triplicate received either nocompound, serial dilutions of 3TC alone, or serial dilutions of 3TC plusN-nonyl-DNJ. At 2, 4, and 6 days after addition of compound (with mediumreplacement on those days), the amount of hepatitis B virus (HBV) DNA inthe culture medium was determined by PCR analysis ofpolyethyleneglycol-sedimented particles. Thus, in these experiments,enveloped particles were not distinguished from nucleocapsids.PCR-amplified products were resolved by agarose gel electrophoresis(1.5% agarose), and the 538 nucleotide fragment was quantified by bandscanning (HP Jet Imager). The amount of HBV recovered from untreatedcells is assumed to be 100%. Data from the 6-day time point arepresented in FIG. 1 as the average values from at least three separateflasks, and the standard error was never greater than 20%, with anaverage error of 12%.

For each of the three time point series tested, the combination of 3TCplus N-nonyl-DNJ was significantly more effective in inhibiting HBVsecretion than either compound alone. Conclusions based upon PCRanalysis alone make it difficult to assign precise IC-50 values. Theextreme sensitivity and delicate nature of PCR, for example, may accountfor the inability to achieve greater than 90% inhibition of HBV by 3TCalone, even at 300 nM. Every experiment included controls to assure thatPCR was performed in a range of concentrations of DNA in which thereaction yields results proportional to the amount of DNA in the sample.Resolution is approximately 3-fold, i.e., 3-fold differences in DNAconcentrations can be detected. The inability to consistently detectless than 3-fold differences probably explains the failure of 3TC aloneto achieve 90% inhibition. This suggests that a very high standard ofinhibition must be met for the PCR to detect inhibition. Consequently,the trend, over three separate time points, is clear: the combinedeffect of 3TC plus N-nonyl-DNJ is greater than that of either compoundalone, or the additive individual effects of each compound. These datasuggest that the IC-50 of 3TC has been moved from about 60 nM to about0.48 nM when 0.016 g/ml N-nonyl-DNJ is present.

EXAMPLE 5 Anti-Hepatitis B Virus Effect of N-nonyl-DNJ Alone in aWoodchuck Model

In order to evaluate the efficacy of N-nonyl-DNJ in combination with 3TC(or other nucleoside or nucleotide analogs) against Hepatitis B virus ina woodchuck animal model, an monotherapy experiment using N-nonyl-DNJalone was first conducted. This was necessary to determine ifN-nonyl-DNJ has any anti-HBV effect in the woodchuck and, if N-nonyl-DNJhas a beneficial effect, to design a combination study based on thedose-response relationship of this drug alone.

Therefore, five groups of four animals each (all groups had both sexes,all but the control had two of each sex) were assigned to 0, 12.5, 25,50, and 100 mg/kg/day with BID oral dosing. These were lab-reared wildanimals. All animals were infected with woodchuck hepatitis virus (WHV)as neonates, and had been tested positive on serological tests for WHVsurface antigen. Blood samples were drawn one week prior to dosing (−1week), immediately before dosing (0 weeks), weekly during dosing (1,2,3, and 4 weeks), and after the end of dosing (5, 6, 8, and 10 weeks).

There are two measures of drug efficacy: reduction in total HBV DNA(measured by quantitative PCR), and reduction in HBV DNA from capsidswith intact surface glycoproteins, which is the active form of the virus(measured by an ELISA-like immune precipitation assay followed byquantitative PCR). Cell culture experiments with N-nonyl-DNJdemonstrated little or no effect of this compound on total HBV DNA, buta marked effect on the immune precipitated DNA (IPDNA). Notsurprisingly, the IPDNA assay is quite variable; as a partialcompensation for this, four assay runs were conducted, each containingsamples from all animals, but different subsets of the study weeks.

To summarize the results, N-nonyl-DNJ had no effect on total HBV DNAmeasurements, which were essentially constant for all dose levels overthe pre-dose and dosed portions of the study. On the other hand, IPDNAlevels were not constant over the study period. The low dose animalstended to have increasing levels of IPDNA over the dosing period (weeks0-4), while high dose animals tended to have decreasing levels of IPDNAover the same period. Fitting a straight line to each animal's weeklyresponses gave a significant difference in the slope of these lines dueto either dose or plasma level of drug. The plasma levels of drug werealso quite variable: animals with the lowest plasma levels in their dosegroup had lower plasma levels than the animals with the highest plasmalevels from the next lower dose group. There were no differences betweenresponses of males and females on any of the measures.

Plasma Levels

There were no clear patterns in the changes in plasma levels ofN-nonyl-DNJ which could be related to week of dosing or time sinceprevious dose. Because the plasma levels within an animal seemedreasonably consistent during dosing, the median plasma level for eachanimal was used for subsequent modeling. The plasma levels for each weekof the dosing period are plotted for each animal vs. dose (a smallamount of random noise is added to the dose level so points which wouldlie on top of each other on the plot can be distinguished) (FIG. 2).

HBV DNA

The total HBV DNA levels were essentially constant over time within eachanimal (data not shown). There was a faint hint of a dose-responserelationship with decreasing levels of virus with increasing levels ofdrug, except that three animals at the highest dose had very high viruslevels. It is not possible to conclude that there is any relationshipbetween dose of N-nonyl-DNJ and total HBV DNA. It is possible that thereare two populations of animals, responders (such as animal r) andnon-responders (animals i, m, and d), but more data would be required topermit a firm conclusion on this point.

Immune Precipitated HBV DNA

Substantial variation existed in the IPDNA assay, both between assayruns and within assay runs (data not shown). Even so, it was possible toobserve and model a slope over weeks 0-4 which is generally increasingfor low dose animals and decreasing for high dose animals. This changein slope was statistically significant (p<0.005).

Before models are fitted to the data, a log transform was appliedbecause: 1) the variation in IPDNA increases with increasing IPDNAvalues; the log transformation gives values with a nearly constantvariation, and 2) it is expected that drug effects will appear as aconstant multiplier of the IPDNA level. Because there are zero values ofIPDNA, a small value (about ½ of the smallest non-zero value) was addedto all values before the log transform.

Two approaches were used to model the changes in slope to week with doseof N-nonyl-DNJ: a linear modeling approach and a nonlinear model. Bothapproaches assume that the (linear) rate of change of the Log(IPDNA)measure over the dosing period is the “right” measure to reflect theeffect of the drug on the virus. Both approaches are fit in stages, andthe first stage is common to both approaches. First, a simple straightline regression model is fit using weeks 0-4 to predictlog(IPDNA_+_(—)10) separately for each animal by run combination. In thesecond stage, the response variable is the slope fitted in the firststage.

For the linear approach, a model is fit with slope to week as theresponse where run is considered a block, dose has a significant effect(almost all of this effect is due to a slope to dose), and the relevanterror for testing the effect of dose is the variation among animalstreated alike (after the adjustment for the runs as blocks). This issimilar to using the calibration data within each run to first adjusteach run's data to a common virus DNA concentration; the difference isthat here the data from the woodchucks are used for the run adjustmentrather than only the calibration data.

For the nonlinear approach, a four parameter logistic model is fit withthe slope to week as the response and the dose as the predictor. Again,run is considered a block, but because no run has all weeks, it is notpossible to fully reflect the blocking in the nonlinear approach. Evenso, the nonlinear model yields an EC50 of 7.88 mg/kg/BID dose. Theaverage maximum slope observed was 2.71 additional Log(IPDNA g/mL)/week,or an increase of about 150%/week, the average minimum slope observedwith N-nonyl-DNJ is 0.31 fewer Log(IPDNA g/mL)/week), or about adecrease of about 25%/week. The slopes, the fitted model, the parameterestimates from the model, and the approximate standard errors for theseparameters are all shown in FIG. 3. The data indicate an approximateeffective monotherapy dose of N-nonyl-DNJ in woodchucks of about 16mg/kg/day. Whether in woodchucks or humans, the effective dose of boththe N-alkyl-DNJ and nucleoside or nucleotide antiviral agentadministered in combination therewith can be administered in two equaldaily subdoses (i.e., B.I.D.).

FIGS. 2 and 3 show letters to indicate animals. Table 4 shows two of theanimal codes, the sex, and the dose.

TABLE 4 Animal Codes, Sex, and Dose Animal Number Letter Code Sex DoseF95343 b F 0 M96364 n M 0 F96304 k F 0 F96301 j F 0 M96285 h M 6.25F96283 g F 6.25 F96391 o F 6.25 M96305 l M 6.25 F96271 f F 12.5 M96256 eM 12.5 M96404 s M 12.5 F96392 p F 12.5 F96163 c F 25 M96414 t M 25F96393 q F 25 M95322 a M 25 M96286 i M 50 F96231 d F 50 F96402 r F 50M96363 m M 50

EXAMPLE 6 Antiviral Study to Test the Activity of N-nonyl-DNJ inCombination with 3TC in a Woodchuck Model of Hepatitis B Virus Infection

The combined activity of N-nonyl-DNJ and the nucleoside analog 3TC canbe assessed using the woodchuck model of hepatitis B virus infection.Twenty-eight woodchucks with persistent woodchuck hepatitis virus (WHV)infection can be utilized. Groups of woodchucks can be treated orallywith 3TC alone (s.i.d.), with N-nonyl-DNJ alone (b.i.d.), or withcombinations of the two drugs. The antiviral activity of the individualdrugs and combinations can be assessed by measuring serum WHV DNA duringtreatment, and comparing the results of treated groups to placebotreated controls.

Twenty-eight woodchucks with established persistent WHV infection can beused, all of which were experimentally infected with WHV during thefirst week of life. All can be WHsAg positive at the time the study isinitiated.

A total of eight experimental groups can be used. Woodchucks in eachgroup can be stratified on the basis of gender, body weight, and age.3TC can be administered orally as an aqueous suspension of Epivir(Glaxo-Wellcome) tablets one time per day. N-nonyl-DNJ can also beadministered orally in aqueous solution, in two divided doses. Treatmentwith both drugs can be followed by the administration of 4 to 5 mls ofsemisynthetic liquid woodchuck diet to insure complete ingestion of thedrugs.

The experimental groups can be as follows:

Group 3TC N-nonyl-DNJ ID No. (mg/kg/day) (mg/kg/day) 1 4 0.0 0.0 2 3 3.00.0 3 3 9.0 0.0 4 3 0.0 4.0 5 3 0.0 12.0 6 4 1.5 2.0 7 4 4.5 6.0 8 4 9.012.0

Woodchucks can be anesthetized (50 mg/kg ketamine, 5 mg/kg zylazine),weighed, and blood samples obtained prior to initial treatment, atweekly intervals during the six week period of treatment, and at 1, 2,and 4 weeks following treatment. Serum can be harvested and divided intoaliquots. One aliquot can be used for analysis of WHV DNA by dot blothybridization and for WHsAg by ELISA. CBCs and clinical biochemicalprofiles can be obtained prior to treatment and at the end of treatment.A second aliquot can be maintained as an archive sample. Other aliquotsof serum can be used for drug analysis and special WHV DNA analyses.

EXAMPLE 7 Preparation of N-[2-(4-trifluoromethylphenyl)-ethyl]-glucamine

Ethanol (40 ml) is added to a pressure shaker bomb. One part of glucoseis dissolved in the solvent followed by one part of2-(4-trifluoromethylphenyl)-ethylamine. Hydrochloric acid is added to apH of about 8 to 9. Wet 50% palladium on carbon 0.1 of a part of glucoseis added and the mixture is agitated at about 40 degrees centigradeunder about 3 atm of hydrogen gas until hydrogen uptake ceases. Thehydrogen is vented and the catalyst is removed by filtration and thefiltrated is washed with ethanol and the washings are added to thefiltrate. The pH of the solution is lowered to about pH=4 withadditional hydrochloric acid and the solvents removed on a rotaryevaporator under reduced pressure.

EXAMPLE 8 Anti-Hepatitis B Virus Activity of N-Substituted-GlucamineCompounds In Vitro

The anti-hepatitis B virus activity and effect on cell viability of anumber of different N-substituted-glucamine compounds is assessed usingan in vitro assay employing chronically hepatitis B virus secretingHepG2.2.15 cells. The method employed is essentially that described inBlock et al. (1994) Proc. Natl. Acad. Sci. USA 91:2235-2239. Thecompounds are of Formula I where R is:[2-(4-trifluoromethylphenyl)-ethyl], 4-(4-trifluoromethylphenyl)-butyl,4-(4-trifluoromethylphenyl)-butane-1-carbonyl,4-(4-trifluoromethyloxyphenyl)-butyl,4-(4-trifluoromethyloxyphenyl)-butane-1-carbonyl, 2-cyclohexylethyl,2-(4-thiapyran)-ethyl, 5-(morpholinyl-pentyl, 4-(4-pyridineoxy)-butyl,3-(3-pyridyl)-propyl, 4-(4-trifluoromethylthiaphenyl)-butyl,7-(trifluoromethylsulfonyl)-heptyl,4-(4-trifluoromethylthiaphenyl)-butyl,8-(trifluoromethylsulfonylamino)-octyl,12,12,12-trifluoro-6,8-dioxa-dodecyl, 10,10,10-trifluoro-5-oxa-decyl,12,12,12,11,11-pentafluoro-6-oxa-dodecyl, 9,9,9-trifluoro-2-oxa-nonyl,5-(4-trifluoromethylphenyl)-4-oxa-butyl,4-(4-trifluoromethylphenyl)-3-oxa-propyl,4-(4-trifluoromethylphenyl)-3-oxa-propanoyl, 5-cyclohexyl-4-oxabutyl,5-(4-trifluoromethoxyphenyl)-4-oxa-butyl and5-(4-trifluoromethylthiaphenyl)-4-oxa-butyl.

The invention being thus described, it will be obvious that the same canbe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications and equivalents as would be obvious to one skilled inthe art are intended to be included within the scope of the followingclaims.

What is claimed is:
 1. A method for treating a hepatitis virus infectionin a mammal, comprising administering to said mammal an anti-hepatitisvirus effective amount of at least one glucamine compound of Formula Ior a pharmaceutically acceptable salt thereof

wherein: R and R⁵ are independently selected from the group consistingof H, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl,arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, perhaloalkylaralkyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkeynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, araloxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylalkenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl,dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl,haloalkoxyalkenyl, haloalkoxyalkynyl, hydroxysulfonealkyl,cycloalkylcarbonyl, arylcarbonyl, cycloalkenylalkylcarbonyl,cycloalkenylalkenylcarbonyl, cycloalkenylalkynylcarbonyl,bicycloalkenylalkylcarbonyl, tricycloalkenylalkylcarbonyl,tetracycloalkenylalkylcarbonyl, bicycloalkenoxyalkylcarbonyl,tricycloalkenoxyalkylcarbonyl, tetracycloalkenyloxyalkylcarbonyl,cycloalkylalkenylcarbonyl, cycloalkylalkynylcarbonyl, aralkylcarbonyl,aralkoxyalkylcarbonyl, aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl,aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl,dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl,haloalkoxyalkenylcarbonyl, haloalkoxyalkynylcarbonyl,hydroxysulfonealkylcarbonyl, R⁷ or R⁸ whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; D and R taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; and wherein the main chain in R or R⁵ contains between one andtwenty atoms.
 2. A method as set forth in claim 1 wherein the main chainof each of R⁷ and R⁸ contains between four and twenty atoms and eitherof R¹X¹ or R⁹X⁹.
 3. A method as set forth in claim 1 wherein R and R⁵are not both hydrido when all of A, B, C and D is hydrido.
 4. A methodas set forth in claim 3 wherein the main chain in R contains between oneand twenty atoms; the main chain of R⁵ containing between four andtwenty atoms; and the main chain of each of R⁷ and R⁸ contains betweenfour and twenty atoms and either of R¹X¹ or R⁹X⁹.
 5. A method as setforth in claim 1 wherein R and R⁵ are independently selected from amongH, alkyl, alkenyl, alkynyl, alkoxyalkyl, arylalkyl, aryloxyalkyl,haloalkyl, hydroxyalkyl, haloalkyloxyalkyl, cycloalkyloxyalkylcycloalkylalkyloxyalkyl.
 6. A method as set forth in claim 5 wherein Rand R⁵ are not both hydrido.
 7. A method as set forth in claim 1 whereinR and R⁵ are not the same when all of A, B, C and D is hydrido.
 8. Amethod as set forth in claim 1 wherein said pharmaceutically acceptablesalt is selected from the group consisting of acetate, adipate,alginate, citrate, phosphate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate.9. A method as set forth in claim 1 wherein R and R⁵ are not the same.10. A method as set forth in claim 1 wherein R and R⁵ are independentlyselected from the group consisting of H, aryloxyalkoxyalkyl,alkylcarbonyloxyalkyl, alkyl, arylcarbonyloxyalkyl, aminoalkyl,alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl,hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl,arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, carbonyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonyl aminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R7 or R⁸.
 11. A method as set forth inclaim 1 wherein R and R⁵ are independently selected from the groupconsisting of alkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl,arylalkyl, arylalkenyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,haloalkyl, haloalkyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,aryl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkylalkynyl,heterocycloalkenyl, heteroarylalkenyl, heteroarylalkynyl, hydroxyalkyl,haloalkoxyalkenyl or haloalkoxyalkynyl.
 12. A method as set forth inclaim 1 wherein R and R⁵ are independently selected from the groupconsisting of aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, carboxyalkyl, aminocarbonylalkyl,aminothiocarbonylalkyl, aminosulfonealkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,aryloxyalkyl, arylthiaalkyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl,aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl,aralkenoxyalkenyl, aryloxyalkenyl, aryloxyalkynyl, hydroxyalkenyl orhydroxyalkynyl.
 13. A method as set forth in claim 1 wherein R and R⁵are independently selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxyalkyl, arylalkyl, heterocycloalkyl, heteroarylalkyl,haloalkyl, haloalkyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,aryl, heterocycloalkenyl, heteroarylalkenyl, haloalkoxyalkenyl, orhaloalkoxyalkynyl.
 14. A method as set forth in claim 1 wherein R and R⁵are independently selected from the group consisting ofaryloxyalkoxyalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,aminocarbonylaminoalkyl, carboxyalkyl, aminocarbonylalkyl,aminosulfonealkyl, heteroaryloxyalkyl, heteroarylthiaalkyl,heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, aralkoxyalkyl,aralkenoxyalkyl or aryloxyalkenyl.
 15. A method as set forth in claim 1wherein R and R⁵ are independently selected from the group consisting ofaryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,alkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkoxyalkylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, aminocarbonylalkylcarbonyl,aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl,arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl,heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,aryloxyalkylcarbonyl, arylthiaalkylcarbonyl, carbonyl,haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkenylcarbonyl,arylcarbonyl, cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl,aryloxyalkynylcarbonyl, hydroxyalkylcarbonyl, hydroxyalkenylcarbonyl,hydroxyalkynylcarbonyl, haloalkoxyalkenylcarbonyl orhaloalkoxyalkynylcarbonyl.
 16. A method as set forth in claim 1 whereinR and R⁵ are independently selected from the group consisting ofalkylcarbonyl, aminoalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkoxyalkylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl,haloalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl,cycloalkenylalkylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, heterocycloalkenylcarbonyl,heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl,hydroxyalkylcarbonyl, haloalkoxyalkenylcarbonyl orhaloalkoxyalkynylcarbonyl.
 17. A method as set forth in claim 1 whereinR and R⁵ are independently selected from the group consisting ofaryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl,carboxyalkylcarbonyl, aminocarbonylalkylcarbonyl,aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl,heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,aryloxyalkylcarbonyl, arylthiaalkylcarbonyl, cycloalkyloxyalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,aryloxyalkenylcarbonyl, aryloxyalkynylcarbonyl, hydroxyalkenylcarbonyl,or hydroxyalkynylcarbonyl.
 18. A method for treating a hepatitis virusinfection in a mammal, comprising administering to said mammal ananti-hepatitis virus effective amount of an antiviral compositioncomprising at least one glucamine compound of Formula I or apharmaceutically acceptable salt thereof

wherein: R and R⁵ are independently selected from the group consistingof H, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl,arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, perhaloalkylaralkyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylalkenlyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl,dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl,haloalkoxyalkenyl, haloalkoxyalkynyl, hydroxysulfonealkyl,cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl,cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, bicycloalkenylalkylcarbonyl,tricycloalkenylalkylcarbonyl, tetracycloalkenylalkylcarbonyl,bicycloalkenoxyalkylcarbonyl, tricycloalkenoxyalkylcarbonyl,tetracycloalkenyloxyalkylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, aralkylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkenylcarbonyl, aryloxyalkenylcarbonyl,aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl,dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl,haloalkoxyalkenylcarbonyl, haloalkoxyalkynylcarbonyl,hydroxysulfonealkylcarbonyl, R⁷ or R⁸, whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; D and E taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; and wherein tile main chain in R or R⁵ contains between one andtwenty atoms; and a pharmaceutically acceptable carrier, diluent, orexcipient.
 19. A method as set forth in claim 18 wherein R and R⁵ areindependently selected from among H, alkyl, alkenyl, alkynyl,alkoxyalkyl, arylalkyl, aryloxyalkyl, haloalkyl, hydroxyalkyl,haloalkyloxyalkyl, cycloalkyloxyalkyl cycloalkylalkyloxyalkyl.
 20. Amethod as set forth in claim 18 wherein R and R⁵ are not both hydridowhen all of A, B, C and D is hydrido.
 21. A method as set forth in claim18 wherein the main chain in R contains between one and twenty atoms;and the main chain of R⁵ containing between four and twenty atoms.
 22. Amethod as set forth in claim 18 wherein said pharmaceutically acceptablesalt is selected from the group consisting of acetate, adipate,alginate, citrate, phosphate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, a camphorate, camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate.23. A method as set forth in claim 18 consisting essentially ofadministering to said mammal an anti-hepatitis virus effective amount ofat least one glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof.
 24. A method as set forth in claim 18comprising administering to said mammal an anti-hepatitis viruseffective amount of an antiviral composition consisting essentially ofat least one glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof.
 25. A method as set forth in claim 18consisting essentially of administering to said mammal an anti-hepatitisvirus effective amount of an antiviral composition consistingessentially of at least one glucamine compound of Formula I or apharmaceutically acceptable salt thereof.
 26. A method as set forth inclaim 18 comprising administering to said mammal an anti-hepatitis viruseffective amount of an antiviral composition containing at least oneglucamine compound of Formula I or a pharmaceutically acceptable saltthereof, said administration being substantially exclusive of theadministration of any antiviral agent comprising a nucleoside,nucleotide, an immunodulator or an immunostimulant.
 27. A method as setforth in claim 18 wherein said administration is substantially exclusiveof the administration of an antiviral agent other than an agent or agentcorresponding to Formula
 1. 28. A method as set forth in claim 18comprising treating a hepatitis B virus infection comprisingadministering to said mammal an anti-hepatitis B virus effective amountof at least one glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof.
 29. A method as set forth in claim 18comprising treating a hepatitis C virus infection comprisingadministering to said mammal an anti-hepatitis C virus effective amountof at least one glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof.
 30. A method as set forth in claim 18 wherein Rand R⁵ are independently selected from the group consisting of hydrido,aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl,alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkoxyalkyl, hydroxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, heterocycloalkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, carbonyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonaylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylalkyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸; provided that not both R andR⁵ are hydrido.
 31. A method as set forth in claim 18 wherein R and R⁵are independently selected from the group consisting of alkyl,aminoalkyl, arylcarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl,hydroxyalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycloalkyl,heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl,heterocyclooxyalkyl, heterocyclothiaalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl,alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl,aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl,haloalkyloxyalkylcarbonyl, cycloalkyl, cycloalkyloxyalkylcarbonyl,alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, alkoxycarbonyl,alkylcarbonyl, aryloxyalkoxyalkylcarbonyl,alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl,aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸; provided that where one of Ror R⁵ is lower alkyl, R and R⁵ are not the same.
 32. A method as setforth in claim 31; provided that R and R⁵ are not the same.
 33. A methodas set forth in claim 18 wherein R is selected from the group consistingof aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl,arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl; and R⁵ is H, alkyl, alkenyl, alkynyl,alkoxyalkyl, arylalkyl, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, haloalkyloxyalkyl, cycloalkyloxyalkylcycloalkylalkyloxyalkyl, R⁷ or R⁸.
 34. A method as set forth in claim 18wherein R and R⁵ are independently selected from the group consisting ofH, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl,arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarboxylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl,carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸.
 35. An N-substitutedglucamine compound of Formula I or a pharmaceutically acceptable saltthereof:

wherein: R and R⁵ are independently selected from the group consistingof aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylalkenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl,hydroxyalkyl, dihydroxyalkyl,hydroxyalkenyl, dihydroxyalkenyl,hydroxyalkynyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylcarbonyl,amino(alkyl), alkanoyl(amino)alkyl, (amino)carbonylalkyl,hydroxysulfonealkyl, (amino)carbonylaminoalkyl, R⁷ or R⁸, whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; D and E taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; wherein the main chain in R or R⁵ contains between one and twentyatoms; and the main chain of each of R⁷ and R⁸ contains between four andtwenty atoms and either of R¹X¹ or R⁹X⁹.
 36. An N-substituted glucaminecompound of Formula I or a pharmaceutically acceptable salt thereof:

wherein: R is selected from the group consisting of alkyl, aminoalkyl,arylcarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl, hydroxyalkyl,arylalkyl, arylalkenyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸, R⁵ is selected from the groupconsisting of aminoalkyl, arylcarbonylaminoalkyl, alkynyl, alkoxyalkyl,hydroxyalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycloalkyl,heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl,heterocyclooxyalkyl, heterocyclothiaalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, aryloxyalkoxyalkylcarbonyl,alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl,aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸,R⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; and D and E taken together with theatoms to which they are attached may form a five or six memberedheterocyclic ring.
 37. An N-substituted glucamine compound of Formula Ior a pharmaceutically acceptable salt thereof:

wherein: R is selected from the group consisting of H,aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl, arylcarbonyloxyalkyl,aminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl,hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl,arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,aryloxyalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, carbonyl,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸, wherein R⁵ is selected fromthe group consisting of aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkynyl, alkoxyalkyl, arylalkenyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸, whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X₁₁)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; D and E taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; wherein the main chain in R or R⁵ contains between one and twentyatoms; and the main chain of each of R⁷ and R⁸ contains between four andtwenty atoms and either of R¹X¹ or R⁹X⁹.
 38. A compound as set forth inclaim 37 wherein R is selected from the group consisting of H, alkyl,alkenyl, alkynyl, alkoxyalkyl, arylalkyl, aryloxyalkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, hydroxyalkyl, haloalkyloxyalkyl,cycloalkyloxyalkyl or cycloalkylalkyloxyalkyl, and R⁵ is selected fromthe group consisting of alkenyl, alkynyl, alkoxyalkyl, aryloxyalkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkyloxyalkyl,cycloalkyloxyalkyl or cycloalkylalkyloxyalkyl.
 39. A compound as setforth in claim 37 wherein R is selected from the group consisting of H,aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl, arylcarbonyloxyalkyl,aminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl,hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl,arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, carbonyl,cycloalkyloxyalkyl, or cycloalkylalkyloxyalkyl, and R⁵ is selected fromthe group consisting of aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl, arylalkenyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl,carbonyl, cycloalkyloxyalkyl, or cycloalkylalkyloxyalkyl.
 40. A compoundas set forth in claim 37 wherein R is selected from the group consistingof alkyl, aminoalkyl, arylcarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, arylalkynyl,heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, orcycloalkylalkyloxyalkyl, and R⁵ is selected from the group consisting ofalkyl, aminoalkyl, arylcarbonylaminoalkyl, alkynyl, alkoxyalkyl,hydroxyalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycloalkyl,heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl,heterocyclooxyalkyl, heterocyclothiaalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, cycloalkyloxyalkyl, or cycloalkylalkyloxyalkyl. 41.An N-substituted glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof:

wherein: R is selected from the group consisting of aryloxyalkoxyalkyl,alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkoxyalkyl,hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,aminothiocarbonylalkyl, aminosulfonealkyl, heterocycloalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl,carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl,alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylalkyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸, wherein R⁵ is selected fromthe group consisting of aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl,aminothiocarbonylaminoalkyl, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, heterocycloalkyl, heteroaryloxyalkyl,heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl,arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl,haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl,alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl,alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl,aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl,carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylalkyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, R⁷ or R⁸, whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; D and E taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; wherein the main chain in R or R⁵ contains between one and twentyatoms; and the main chain of each of R⁷ and R⁸ contains between four andtwenty atoms and either of R¹X¹ or R⁹X⁹.
 42. A pharmaceuticalcomposition comprising an anti-viral compound comprising anN-substituted glucamine compound or a pharmaceutically acceptable saltthereof and another antiviral compound selected from the groupconsisting of a nucleoside, a nucleotide, an immunomodulator, animmunostimulant, and mixtures thereof, said glucamine compoundcorresponding to Formula I:

wherein: R and R⁵ are independently selected from the group consistingof H, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl,arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, perhaloalkylaralkyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylalkenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl,dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl,haloalkoxyalkenyl, haloalkoxyalkynyl, hydroxysulfonealkyl,cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl,cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, bicycloalkenylalkylcarbonyl,tricycloalkenylalkylcarbonyl, tetracycloalkenylalkylcarbonyl,bicycloalkenoxyalkylcarbonyl, tricycloalkenoxyalkylcarbonyl,tetracycloalkenyloxyalkylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, aralkylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl,aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl,dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl,haloalkoxyalkenylcarbonyl, haloalkoxyalkynylcarbonyl,hydroxysulfonealkylcarbonyl, R⁷ or R⁸, whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; and D and E taken together with theatoms to which they are attached may form a five or six memberedheterocyclic ring.
 43. A composition as set forth in claim 42 wherein Rand R⁵ are not both hydrido when all of A, B, C and D is hydrido.
 44. Acomposition as set forth in claim 42 wherein the main chain in Rcontains between one and twenty atoms; and the main chain of R⁵ containsbetween four and twenty atoms.
 45. A composition as set forth in claim42 wherein R and R⁵ are independently selected from among H, alkyl,alkenyl, alkynyl, alkoxyalkyl, arylalkyl, aryloxyalkyl, aryloxyalkyl,haloalkyl, hydroxyalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, orcycloalkylalkyloxyalkyl.
 46. A composition as set forth in claim 42comprising a first amount of said compound of Formula I and a secondamount of an antiviral compound selected from the group consisting of anucleoside antiviral compound, a nucleotide antiviral compound, animmunomodulator, an immunostimulant, and mixtures thereof, wherein saidfirst and second amounts of said compounds together comprise ananti-hepatitis virus effective amount of said compounds.
 47. Acomposition a set forth in claim 42 further comprising apharmaceutically acceptable, carrier, diluent or excipient.
 48. A saltof an N-substituted glucamine compound and an antiviral compoundselected from the group consisting of a nucleoside having an acid moietyand a nucleotide, said glucamine compound corresponding to Formula I:

wherein: R and R⁵ are independently selected from the group consistingof H, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl,arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, perhaloalkylaralkyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylalkenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl,dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl,haloalkoxyalkenyl, haloalkoxyalkynyl, hydroxysulfonealkyl,cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl,cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, bicycloalkenylalkylcarbonyl,tricycloalkenylalkylcarbonyl, tetracycloalkenylalkylcarbonyl,bicycloalkenoxyalkylcarbonyl, tricycloalkenoxyalkylcarbonyl,tetracycloalkenyloxyalkylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, aralkylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl,aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl,dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl,haloalkoxyalkenylcarbonyl, haloalkoxyalkynylcarbonyl,hydroxysulfonealkylcarbonyl, R⁷ or R⁸, whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)^(r)(R¹²X¹²)_(p)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; and D and E taken together with theatoms to which they are attached may form a five or six memberedheterocyclic ring.
 49. A pharmaceutical composition comprising anantiviral effective amount of the salt of claim
 48. 50. A pharmaceuticalcomposition comprising the salt of claim 48 further comprising apharmaceutically acceptable carrier, diluent or excipient.
 51. Apharmaceutical composition comprising the salt of claim 48 furthercomprising an antiviral compound selected from the group consisting of anucleoside antiviral compound, a nucleotide antiviral compound, andimmunomodulator, an immunostimulant, and mixtures thereof.
 52. A methodfor treating a hepatitis virus infection in a mammal, comprisingadministering to said mammal a first amount of at least oneN-substituted glucamine compound of Formula I or a pharmaceuticallyacceptable salt thereof:

wherein: R and R⁵ are independently selected from the group consistingof H, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl,arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl,aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl,alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl,aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl,heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl,haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl,cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl,arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl,aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminolkylcarbonyl,arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl,aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl,arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl,aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl,aminosulfonealkylcarbonyl, arylalkynylcarbonyl,heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl,heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl,arylthiaalkylcarbonyl, monohaloalkylcarbonyl,cycloalkylalkyloxyalkylcarbonyl, perhaloalkylaralkyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl,cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl,tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl,tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl,cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl,aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl,heteroarylalkenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl,dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl,haloalkoxyalkenyl, haloalkoxyalkynyl, hydroxysulfonealkyl,cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl,cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl,cycloalkenylalkynylcarbonyl, bicycloalkenylalkylcarbonyl,tricycloalkenylalkylcarbonyl, tetracycloalkenylalkylcarbonyl,bicycloalkenoxyalkylcarbonyl, tricycloalkenoxyalkylcarbonyl,tetracycloalkenyloxyalkylcarbonyl, cycloalkylalkenylcarbonyl,cycloalkylalkynylcarbonyl, aralkylcarbonyl, aralkoxyalkylcarbonyl,aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl,aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl,heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl,aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl,dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl,haloalkoxyalkenylcarbonyl, haloalkoxyalkynylcarbonyl,hydroxysulfonealkylcarbonyl, R⁷ or R⁸, whereinR⁷=R¹X¹(R²X²)_(m)(R³X³)_(n)(R⁴X⁴)_(p)R¹³;R⁸=R⁹X⁹(R¹⁰X¹⁰)_(q)(R¹¹X¹¹)_(r)(R¹²X¹²)_(s)R¹³ R¹ and R⁹ areindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, hydrogen or haloalkyl; R², R³, R⁴, R¹⁰, R¹¹, R¹² andR¹³ are independently selected from the group consisting of alkylene,alkenylene, alkynylene or haloalkylene; X¹, X², X³, X⁴, X⁹, X¹⁰, X¹¹ andX¹² are independently oxygen, sulfur, sulfoxide or sulfone; m, n, p, q,r and s are independently 0, 1, 2 or 3; m+n+p≦3 q+r+s≦3 A, B, C, D and Eare independently hydrido, lower alkyl or acyl; A and B taken togetherwith the atoms to which they are attached may form a five or sixmembered heterocyclic ring; B and C taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; C and D taken together with the atoms to which they are attachedmay form a five or six membered heterocyclic ring; C and E takentogether with the atoms to which they are attached may form a five orsix membered heterocyclic ring; D and E taken together with the atoms towhich they are attached may form a five or six membered heterocyclicring; wherein the main chain in R or R⁵ contains between one and twentyatoms; the main chain of each of R⁷ and R⁸ contains between four andtwenty atoms and either of R¹X¹ or R⁹X⁹; and a second amount of anantiviral compound selected from the group consisting of a nucleosideantiviral compound, a nucleotide antiviral compound, an immunomodulator,an immunostimulant, and mixtures thereof.
 53. A method as set forth inclaim 52 wherein said first and second amounts of said compoundstogether comprise an anti-hepatitis virus effective amount of saidcompounds.
 54. A method as set forth in claim 52 wherein said nucleosideor nucleotide antiviral compound is selected from the group consistingof:(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;(−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC);(−)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine(FTC); (−)2′,3′, dideoxy-3′-thiacytidine [(−)-SddC];1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC);1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosinetriphosphate (FIACTP);1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU);1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide;2′,3′-dideoxy-3′-fluoro-5-methyl-dexocytidine (FddMeCyt);2′,3′-dideoxy-3′-chloro-5-methyl-dexocytidine (ClddMeCyt);2′,3′-dideoxy-3′-amino-5-methyl-dexocytidine (AddMeCyt);2′,3′-dideoxy-3′-fluorothymidine (FddThd);2′,3′-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);2′,3′-dideoxy-beta-L-5-thiacytidine; 2′,3′-dideoxy-beta-L-5-cytidine(beta-L-ddC); 9-(1,3-dihydroxy-2-propoxymethyl)guanine;2′-deoxy-3′-thia-5-fluorocytosine;2-amino-1,9-(2-hydroxymethyl-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one(gancyclovir); 2-[2-(2-amino-9H-purin-9y)ethyl]-1,3-propandil diacetate(famciclovir);2-amino-1,9-dihydro-9-[(2-hydroxy-ethoxy)methyl]6H-purin-6-one(acyclovir); 9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine(penciclovir); 9-(4-hydroxy-3-hydroxymethyl-but-1-yl)-6-deoxy-guanine,diacetate (famciclovir); 3′-azido-3′-deoxythymidine (AZT);9-(2-phosphonyl-methoxyethyl)-2′,6′-diaminopurine-2′,3′-dideoxyriboside;9-(2-phosphonylmethoxyethyl)adenine (PMEA); acyclovir triphosphate(ACVTP); D-carbocyclic-2′-deoxyguanosine (CdG); dideoxy-cytidine;dideoxy-cytosine (ddC); dideoxy-guanine (ddG); dideoxy-inosine (ddI);E-5-(2-bromovinyl)-2′-deoxyuridine triphosphate;fluoro-arabinofuranosyl-iodouracil;1-(2′-deoxy-2′-fluoro-1-beta-D-arabinofuranosyl)-5-iodo-uracil (FIAU);stavudine; 9-beta-D-arabinofuranosyl-9H-purine-6-amine monohydrate(Ara-A); 9-beta-D-arabinofuranosyl-9H-purine-6-amine-5′-monophosphatemonohydrate (Ara-AMP); 2-deoxy-3′-thia-5-fluorocytidine;2′,3′-dideoxy-guanine; and 2′,3′-dideoxy-guanosine.
 55. A method as setforth in claim 52 comprising administering to said mammal from about 0.1mg/kg/day to about 100 mg/kg/day of at least one N-substituted glucaminecompound of Formula I or a pharmaceutically acceptable salt thereof; andfrom about 0.1 mg/person/day to about 500 mg/person/day of a compoundselected from the group consisting of a nucleoside antiviral compound, anucleotide antiviral compound, and a mixture thereof.
 56. A method asset forth in claim 55 comprising administering between about 0.1mg/person/day and about 500 mg/person/day of(−)-2′-deoxy-3′-thiocytidine-5′-triphosphate.
 57. A method as set forthin claim 52 comprising treating a hepatitis B virus infection comprisingadministering to said mammal an anti-hepatitis B virus effective amountof at least one N-substituted glucamine compound of Formula I or apharmaceutically acceptable salt thereof.
 58. A method as set forth inclaim 52 comprising treating a hepatitis C virus infection comprisingadministering to said mammal an anti-hepatitis C virus effective amountof at least one N-substituted glucamine compound of Formula I or apharmaceutically acceptable salt thereof.